Trial Outcomes & Findings for Oral HYCAMTIN Plus Whole Brain Radiation Therapy In Treatment Of Brain Metastases Resulting From Non-Small Lung Cancer (NCT NCT00390806)

NCT ID: NCT00390806

Last Updated: 2014-01-20

Results Overview

Overall survival is defined as the time from randomization until the date of death due to any cause. The date of last contact was used for those participants who had not died or were lost to follow-up. These participants were classified as having been censored.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 472 participants
• Primary outcome timeframe: From the time of Randomization until the date of death due to any cause (up to 195 weeks)
• Results posted on: 2014-01-20

Participant Flow

Participant milestones

Measure	Chemoradiation: Topotecan Plus WBRT Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Overall Study STARTED	236	236
Overall Study Ongoing	4	2
Overall Study COMPLETED	206	204
Overall Study NOT COMPLETED	30	32

Reasons for withdrawal

Measure	Chemoradiation: Topotecan Plus WBRT Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Overall Study Lost to Follow-up	7	6
Overall Study Protocol Violation	2	2
Overall Study Withdrawal by Subject	12	15
Overall Study Investigator Decision	4	6
Overall Study Death	1	0
Overall Study Physician Decision	0	1
Overall Study Ongoing	4	2

Baseline Characteristics

Oral HYCAMTIN Plus Whole Brain Radiation Therapy In Treatment Of Brain Metastases Resulting From Non-Small Lung Cancer

Baseline characteristics by cohort

Measure	Chemoradiation: Topotecan Plus WBRT n=236 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=236 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.	Total n=472 Participants Total of all reporting groups
Age, Continuous	59.4 Years STANDARD_DEVIATION 8.56 • n=5 Participants	57.8 Years STANDARD_DEVIATION 8.65 • n=7 Participants	58.6 Years STANDARD_DEVIATION 8.63 • n=5 Participants
Sex: Female, Male Female	84 Participants n=5 Participants	78 Participants n=7 Participants	162 Participants n=5 Participants
Sex: Female, Male Male	152 Participants n=5 Participants	158 Participants n=7 Participants	310 Participants n=5 Participants
Race/Ethnicity, Customized African American/African Heritage (Her.)	3 participants n=5 Participants	1 participants n=7 Participants	4 participants n=5 Participants
Race/Ethnicity, Customized Central/South Asian Heritage	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Japanese/East Asian Heritage/South East Asian Her.	0 participants n=5 Participants	3 participants n=7 Participants	3 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized White	230 participants n=5 Participants	232 participants n=7 Participants	462 participants n=5 Participants
Race/Ethnicity, Customized Asian & White	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants

PRIMARY outcome

Timeframe: From the time of Randomization until the date of death due to any cause (up to 195 weeks)

Population: Intent-to-Treat (ITT) Population: all randomized participants. Participants were analyzed by the treatment to which they were randomized, even if this differed from the treatment they actually received.

Overall survival is defined as the time from randomization until the date of death due to any cause. The date of last contact was used for those participants who had not died or were lost to follow-up. These participants were classified as having been censored.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=236 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=236 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Overall Survival	4.0 months Interval 3.4 to 4.8	3.6 months Interval 3.0 to 4.0

SECONDARY outcome

Timeframe: Month 6

Population: ITT Population

Six-month survival is defined as the percentage of participants alive at 6 months following randomization. The date of last contact was used for those participants who had not died or were lost to follow-up. These participants were classified as having been censored.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=236 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=236 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Six-month Survival	36 percentage of participants	28 percentage of participants

SECONDARY outcome

Timeframe: From the time of Randomization until the time of CR or PR (up to 75 weeks)

Population: ITT Population

The number of participants achieving either a CR or PR, per World Health Organization (WHO) Criteria, in the CNS was assessed. CR is defined as the complete disappearance of all known measurable (Must be accurately measured in >=1 dimension) and nonmeasurable disease, without clinical, laboratory, or radiological evidence of recurrence for at least 4 weeks. CR may have been defined in participants with measurable and/or non-measurable disease at Screening. PR is defined as at least a 50% decrease in the sum of the products of the greatest length and perpendicular width of all measurable disease with no clear increase in nonmeasurable disease in participants without measurable disease. In both cases, there must have been no appearance of new disease, and no clinical, laboratory, or radiological evidence of disease progression for at least 4 weeks. Assessment of response was performed by the investigator and was based on unconfirmed responses.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=236 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=236 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With a Complete Response (CR) or a Partial Response (PR) (Central Nervous System [CNS]-Radiologic) Complete response	23 participants	11 participants
Number of Participants With a Complete Response (CR) or a Partial Response (PR) (Central Nervous System [CNS]-Radiologic) Partial response	63 participants	61 participants

SECONDARY outcome

Timeframe: From the time of Randomization until the first documented evidence of CR or PR (up to 75 weeks)

Population: ITT Population. Only those participants with a CR, PR, or a missing response were assessed. TTR was analyzed with censoring for extended loss to follow-up to account for two or more missed response assessments before a TTR event. The date of the last adequate CNS assessment before extended loss to follow-up was used for censored participants.

TTR is defined as the time from Randomization until the first documented evidence of CR or PR in the CNS. CR is defined as the complete disappearance of all known measurable (Must be accurately measured in >=1 dimension) and nonmeasurable disease, without clinical, laboratory, or radiological evidence of recurrence for at least 4 weeks. CR may have been defined in participants with measurable and/or non-measurable disease at Screening. PR is defined as at least a 50% decrease in the sum of the products of the greatest length and perpendicular width of all measurable disease with no clear increase in nonmeasurable disease in participants without measurable disease. In both cases, there must have been no appearance of new disease, and no clinical, laboratory, or radiological evidence of disease progression for at least 4 weeks. Assessment of response was performed by the investigator and was based on unconfirmed responses.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=173 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=170 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Time to Response (TTR) (CNS-radiologic)	8.0 weeks Interval 7.7 to 8.1	8.1 weeks Interval 6.0 to 8.1

SECONDARY outcome

Timeframe: From the time of Randomization until the first documented sign of disease progression (up to 75 weeks)

Population: ITT Population

TTP is defined as the time from Randomization until the first documented sign of disease progression in the CNS. Progressive disease (PD) is defined as an increase >=25% in any measurable lesion or, in participants with non-measurable disease only, an estimation of an increase >=25%. In both cases, determination of progression included the appearance of any new lesions, or signification worsening of conditions presumed to be related to malignancy. Participants with clinical or laboratory evidence of possible disease progression were to be evaluated radiologically. TTP was analyzed with censoring for extended loss to follow-up to account for two or more missed assessments before a TTP event. The date of the last adequate CNS assessment before extended loss to follow-up was used for censored participants.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=236 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=236 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Time to Progression (TTP) (CNS-radiologic)	9.7 weeks Interval 8.1 to 13.9	9.7 weeks Interval 8.3 to 10.9

SECONDARY outcome

Timeframe: From the time of Randomization until the first documented sign of disease progression (up to 75 weeks)

Population: ITT Population

TTP is defined as the time from Randomization until the first documented sign of disease progression in all sites of disease. Progressive disease (PD) is defined as an increase >=25% in any measurable lesion or, in participants with non-measurable disease only, an estimation of an increase >=25%. In both cases, determination of progression included the appearance of any new lesions, or signification worsening of conditions presumed to be related to malignancy. Participants with clinical or laboratory evidence of possible disease progression were to be evaluated radiologically. TTP was analyzed with censoring for extended loss to follow-up to account for two or more missed assessments before a TTP event. The date of the last adequate CNS assessment before extended loss to follow-up was used for censored participants.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=236 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=236 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Time to Progression (TTP) (All Sites of Disease-radiologic)	8.0 weeks Interval 6.7 to 8.7	7.7 weeks Interval 6.1 to 8.1

SECONDARY outcome

Timeframe: Months 1 and 3

Population: ITT Population. Only those participants who were assessed for the indicated sign and symptom at the indicated time point were analyzed.

Neurological signs and symptoms data were derived from a participant-reported diary. The participants were asked to assess the following signs and symptoms on a scale of none, mild, moderate, or severe at Months 1 and 3: headache, problems with balance/coordination (PB/C), leg weakness, arm weakness, loss of feeling/numbness (LofF/N), speech difficulty (SD), confusion, loss of memory (LofM), drowsiness, nausea, vomiting, dizziness, visual problems (VP), seizures, leg/ankle swelling (L/AS), heart burn, difficulty sleeping (DS), tiredness, and appetite/weight gain (A/WG).

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=179 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=189 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 VP, Month 3, none, n=109, 111	72 participants	69 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Tiredness, Month 3, none, n=109, 111	28 participants	21 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Tiredness, Month 3, mild, n=109, 111	52 participants	42 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Tiredness, Month 3, moderate, n=109, 111	19 participants	32 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Tiredness, Month 3, severe, n=109, 111	10 participants	16 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 A/WG, Month 1, none, n=179, 188	107 participants	113 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 A/WG, Month 1, mild, n=179, 188	42 participants	41 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Headache, Month 1, none, n=179, 189	93 participants	106 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Headache, Month 1, mild, n=179, 189	71 participants	68 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Headache, Month 1, moderate, 179, 189	11 participants	13 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Headache, Month 1, severe, 179, 189	4 participants	2 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Headache, Month 3, none, n=109, 111	69 participants	53 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Headache, Month 3, mild, n=109, 111	33 participants	41 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Headache, Month 3, moderate, n=109, 111	5 participants	14 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Headache, Month 3, severe, n=109, 111	2 participants	3 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 PB/C, Month 1, none, n=179, 188	84 participants	79 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 PB/C, Month 1, mild, n=179, 188	66 participants	71 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 PB/C, Month 1, moderate, n=179, 188	22 participants	30 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 PB/C, Month 1, severe, n=179, 188	7 participants	8 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 PB/C, Month 3, none, n=109, 111	69 participants	46 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 PB/C, Month 3, mild, n=109, 111	28 participants	36 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 PB/C, Month 3, moderate, n=109, 111	10 participants	18 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 PB/C, Month 3, severe, n=109, 111	2 participants	11 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Leg weakness, Month 1, none, n=179, 188	47 participants	59 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Leg weakness, Month 1, mild, n=179, 188	73 participants	72 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Leg weakness, Month 1, moderate, n=179, 188	41 participants	41 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Leg weakness, Month 1, severe, n=179, 188	18 participants	16 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Leg weakness, Month 3, none, n=109, 111	28 participants	34 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Leg weakness, Month 3, mild, n=109, 111	51 participants	37 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Leg weakness, Month 3, moderate, n=109, 111	20 participants	19 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Leg weakness, Month 3, severe, n=109, 111	10 participants	21 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Arm weakness, Month 1, none, n=179, 188	96 participants	97 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Arm weakness, Month 1, mild, n=179, 188	55 participants	60 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Arm weakness, Month 1, moderate, n=179, 188	23 participants	18 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Arm weakness, Month 1, severe, n=179, 188	5 participants	13 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Arm weakness, Month 3, none, n=109, 111	60 participants	53 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Arm weakness, Month 3, mild, n=109, 111	39 participants	34 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Arm weakness, Month 3, molderate, n=109, 111	8 participants	16 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Arm weakness, Month 3, severe, n=109, 111	2 participants	8 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofF/N, Month 1, none, n=179, 188	101 participants	11 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofF/N, Month 1, mild, n=179, 188	53 participants	43 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofF/N, Month 1, moderate, n=179, 188	17 participants	25 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofF/N, Month 1, severe, n=179, 188	8 participants	9 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofF/N, Month 3, none, n=109, 111	73 participants	66 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofF/N, Month 3, mild, n=109, 111	28 participants	27 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofF/N, Month 3, moderate, n=109, 111	3 participants	11 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofF/N, Month 3, severe, n=109, 111	5 participants	7 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 SD, Month 1, none, n=179, 188	151 participants	137 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 SD, Month 1, mild, n=179, 188	16 participants	40 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 SD, Month 1, moderate, n=179, 188	9 participants	9 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 SD, Month 1, severe, n=179, 188	3 participants	2 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 SD, Month 3, none, n=109, 110	94 participants	78 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 SD, Month 3, mild, n=109, 110	11 participants	22 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 SD, Month 3, moderate, n=109, 110	2 participants	8 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 SD, Month 3, severe, n=109, 110	2 participants	2 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Confusion, Month 1, none, n=179, 188	150 participants	148 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Confusion, Month 1, mild, n=179, 188	20 participants	32 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Confusion, Month 1, moderate, n=179, 188	6 participants	7 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Confusion, Month 1, severe, n=179, 188	3 participants	1 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Confusion, Month 3, none, n=109, 110	99 participants	71 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Confusion, Month 3, mild, n=109, 110	7 participants	29 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Confusion, Month 3, moderate, n=109, 110	2 participants	9 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Confusion, Month 3, severe, n=109, 110	1 participants	1 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofM, Month 1, none, n=179, 188	149 participants	141 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofM, Month 1, mild, n=179, 188	20 participants	41 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofM, Month 1, moderate, n=179, 188	8 participants	5 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofM, Month 1, severe, n=179, 188	2 participants	1 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofM, Month 3, none, n=109, 110	93 participants	78 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofM, Month 3, mild, n=109, 110	14 participants	25 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofM, Month 3, moderate, n=109, 110	1 participants	6 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 LofM, Month 3, severe, n=109, 110	1 participants	1 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Drowsiness, Month 1, none, n=179, 188	90 participants	96 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Drowsiness, Month 1, mild, n=179, 188	55 participants	59 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Drowsiness, Month 1, moderate, n=179, 188	25 participants	26 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Drowsiness, Month 1, severe, n=179, 188	9 participants	7 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Drowsiness, Month 3, none, n=109, 111	50 participants	44 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Drowsiness, Month 3, mild, n=109, 111	42 participants	40 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Drowsiness, Month 3, moderate, n=109, 111	15 participants	15 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Drowsiness, Month 3, severe, n=109, 111	2 participants	12 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Nausea, Month 1, none, n=179, 188	125 participants	142 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Nausea, Month 1, mild, n=179, 188	38 participants	36 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Nausea, Month 1, moderate, n=179, 188	12 participants	10 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Nausea, Month 1, severe, n=179, 188	4 participants	0 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Nausea, Month 3, none, n=109, 111	70 participants	73 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Nausea, Month 3, mild, n=109, 111	31 participants	29 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Nausea, Month 3, moderate, n=109, 111	7 participants	6 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Nausea, Month 3, severe, n=109, 111	1 participants	3 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Vomiting, Month 1, none, n=179, 188	153 participants	164 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Vomiting, Month 1, mild, n=179, 188	20 participants	19 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Vomiting, Month 1, moderate, n=179, 188	4 participants	4 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Vomiting, Month 1, severe, n=179, 188	2 participants	1 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Vomiting, Month 3, none, n=109, 111	89 participants	91 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Vomiting, Month 3, mild, n=109, 111	15 participants	15 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Vomiting, Month 3, moderate, n=109, 111	4 participants	3 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Vomiting, Month 3, severe=109, 111	1 participants	2 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Dizziness, Month 1, none, n=179, 188	96 participants	94 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Dizziness, Month 1, mild, n=179, 188	58 participants	70 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Dizziness, Month 1, moderate, n=179, 188	22 participants	21 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Dizziness, Month 1, severe, n=179, 188	3 participants	3 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Dizziness, Month 3, none, n=109, 111	64 participants	54 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Dizziness, Month 3, mild, n=109, 111	35 participants	36 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Dizziness, Month 3, moderate, n=109, 111	7 participants	14 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Dizziness, Month 3, severe, n=109, 111	3 participants	7 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 VP, Month 1, none, n=179, 188	103 participants	117 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 VP, Month 1, mild, n=179, 188	54 participants	53 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 VP, Month 1, moderate, n=179, 188	17 participants	16 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 VP, Month 1, severe, n=179, 188	5 participants	2 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 VP, Month 3, mild, n=109, 111	29 participants	28 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 VP, Month 3, moderate, n=109, 111	7 participants	10 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 VP, Month 3, severe, n=109, 111	1 participants	4 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Seizures, Month 1, none, n=179, 188	173 participants	179 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Seizures, Month 1, mild, n=179, 188	5 participants	7 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Seizures, Month 1, moderate, n=179, 188	1 participants	2 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Seizures, Month 1, severe, n=179, 188	0 participants	0 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Seizures, Month 3, none, n=109, 110	108 participants	102 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Seizures, Month 3, mild, n=109, 110	0 participants	4 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Seizures, Month 3, moderate, n=109, 110	1 participants	3 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Seizures, Month 3, severe, n=109, 110	0 participants	1 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 L/AS, Month 1, none, n=179, 188	141 participants	138 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 L/AS, Month 1, mild, n=179, 188	21 participants	29 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 L/AS, Month 1, moderate, n=179, 188	12 participants	15 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 L/AS, Month 1, severe, n=179, 188	5 participants	6 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 L/AS, Month 3, none, n=109, 111	86 participants	85 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 L/AS, Month 3, mild, n=109, 111	19 participants	19 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 L/AS, Month 3, moderate, n=109, 111	3 participants	6 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 L/AS, Month 3, severe, n=109, 111	1 participants	1 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Heartburn, Month 1, none, n=179, 188	142 participants	151 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Heartburn, Month 1, mild, n=179, 188	26 participants	27 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Heartburn, Month 1, moderate, n=179, 188	9 participants	9 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Heartburn, Month 1, severe, n=179, 188	2 participants	1 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Heartburn, Month 3, none, n=109, 111	87 participants	86 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Heartburn, Month 3, mild, n=109, 111	16 participants	18 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Heartburn, Month 3, moderate, n=109, 111	4 participants	6 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Heartburn, Month 3, severe, n=109, 111	2 participants	1 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 DS, Month 1, none, n=179, 188	112 participants	109 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 DS, Month 1, mild, n=179, 188	41 participants	48 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 DS, Month 1, moderate, n=179, 188	15 participants	24 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 DS, Month 1, severe, n=179, 188	11 participants	7 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 DS, Month 3, none, n=109, 110	78 participants	71 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 DS, Month 3, mild, n=109, 110	20 participants	23 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 DS, Month 3, moderate, n=109, 110	8 participants	12 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 DS, Month 3, severe, n=109, 110	3 participants	4 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Tiredness, Month 1, none, n=179, 188	42 participants	42 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Tiredness, Month 1, mild, n=179, 188	75 participants	85 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Tiredness, Month 1, moderate, n=179, 188	46 participants	44 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 Tiredness, Month 1, severe, n=179, 188	16 participants	17 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 A/WG, Month 1, moderate, n=179, 188	19 participants	29 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 A/WG, Month 1, severe, n=179, 188	11 participants	5 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 A/WG, Month 3, none, n=108, 111	71 participants	73 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 A/WG, Month 3, mild, n=108, 111	27 participants	23 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 A/WG, Month 3, moderate, n=108, 111	4 participants	11 participants
Number of Participants Who Ranked Each Individual Indicated Neurological Sign and Symptom as None, Mild, Moderate, or Severe at Months 1 and 3 A/WG, Month 3, severe, n=108, 111	6 participants	4 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants for the neurological sign and symptom of level of consciousness and assigned each participant to one of the following categories: normal; somnolence or sedation not interfering with function (not intefering); somnolence or sedation interfering with function, but not activities of daily living (ADLs) (interfering); obtundation or stupor, difficult to arouse, inteferring with ADLs (obtundation or stupor); coma.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Baseline, normal, n=230, 228	219 participants	216 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Month 1, normal, n=178, 180	171 participants	169 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Month 3, normal, n=109, 107	102 participants	92 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Baseline, not interfering, n=230, 228	7 participants	9 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Month 1, not interfering, n=178, 180	5 participants	7 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Month 3, not interfering, n=109, 107	3 participants	8 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Baseline, interfering, n=230, 228	3 participants	3 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Month 1, interfering, n=178, 180	0 participants	4 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Month 3, interfering, n=109, 107	3 participants	5 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Baseline, obtundation and stupor, n=230, 228	1 participants	0 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Month 1, obtundation and stupor, n=178, 180	2 participants	0 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Level of Consciousness at Baseline, Month 1, and Month 3 Month 3, obtundation and stupor, n=109, 107	1 participants	2 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

The investigator (per Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) assessed participants for headache and assigned each participant to one of the following categories: absent, Grade (G) 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Headache at Baseline, Month 1, and Month 3 Baseline, absent, n=230, 228	141 participants	146 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Headache at Baseline, Month 1, and Month 3 Month 1, absent, n=178, 180	126 participants	127 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Headache at Baseline, Month 1, and Month 3 Month 3, absent, n=109, 107	85 participants	74 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Headache at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 228	62 participants	55 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Headache at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 180	43 participants	38 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Headache at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	17 participants	23 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Headache at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 228	25 participants	23 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Headache at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 180	9 participants	14 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Headache at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	7 participants	10 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Headache at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 228	2 participants	4 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Headache at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 180	0 participants	1 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

The investigator (per CTCAE, version 3.0) assessed participants for dizziness/lightheadedness and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Baseline, absent, n=230, 228	160 participants	151 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Month 1, absent, n=178, 180	124 participants	128 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Month 3, absent, n=109, 107	76 participants	76 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 228	45 participants	47 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 180	44 participants	36 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	21 participants	20 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 228	21 participants	26 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 180	7 participants	14 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	9 participants	9 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 228	4 participants	4 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 180	3 participants	2 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Dizziness/Lightheadedness at Baseline, Month 1, and Month 3 Month 3, Grade 3, n=109, 107	3 participants	2 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

The investigator (per CTCAE, version 3.0) assessed participants for vertigo and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Baseline, absent, n=230, 228	180 participants	173 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Month 1, absent, n=178, 180	148 participants	150 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Month 3, absent, n=109, 107	90 participants	86 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 228	26 participants	30 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 180	19 participants	19 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	14 participants	13 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 228	19 participants	22 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 180	7 participants	9 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	4 participants	6 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 228	5 participants	3 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 180	3 participants	2 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Month 3, Grade 3, n=109, 107	1 participants	2 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Vertigo at Baseline, Month 1, and Month 3 Month 1, Grade 4, n=178, 180	1 participants	0 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

The investigator (per CTCAE, version 3.0) assessed participants for nausea/vomiting and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Baseline, absent, n=230, 228	203 participants	192 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Month 1, absent, n=178, 180	151 participants	162 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Month 3, absent, n=109, 107	88 participants	93 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 228	19 participants	22 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 180	20 participants	15 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	14 participants	11 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 228	7 participants	10 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 180	6 participants	3 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	6 participants	3 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 228	1 participants	4 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 180	1 participants	0 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Nausea/Vomiting at Baseline, Month 1, and Month 3 Month 3, Grade 5, n=109, 107	1 participants	0 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

The investigator (per CTCAE, version 3.0) assessed participants for visual problem and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Baseline, absent, n=230, 228	181 participants	189 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Month 1, absent, n=178, 180	148 participants	154 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Month 3, absent, n=109, 107	93 participants	93 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 228	22 participants	25 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 180	16 participants	19 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	12 participants	10 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 228	20 participants	13 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 180	11 participants	6 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	4 participants	3 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 228	5 participants	1 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 180	2 participants	1 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Month 3, Grade 3, n=109, 107	0 participants	1 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Baseline, Grade 4, n=230, 228	2 participants	0 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Visual Problem at Baseline, Month 1, and Month 3 Month 1, Grade 4, n=178, 180	1 participants	0 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

The investigator (per CTCAE, version 3.0) assessed participants for seizure and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Seizure at Baseline, Month 1, and Month 3 Baseline, absent, n=230, 228	218 participants	216 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Seizure at Baseline, Month 1, and Month 3 Month 1, absent, n=178, 180	175 participants	178 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Seizure at Baseline, Month 1, and Month 3 Month 3, absent, n=109, 107	109 participants	101 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Seizure at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 228	4 participants	6 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Seizure at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 180	2 participants	1 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Seizure at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	0 participants	4 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Seizure at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 228	6 participants	6 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Seizure at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 180	1 participants	1 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Seizure at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	0 participants	2 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Seizure at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 228	1 participants	0 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Seizure at Baseline, Month 1, and Month 3 Baseline, Grade 4, n=230, 228	1 participants	0 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

The investigator (per CTCAE, version 3.0) assessed participants for other neurological symptoms and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=229 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Baseline, absent, n=229, 228	219 participants	214 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Month 1, absent, n=177, 180	165 participants	171 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Month 3, absent, n=109, 107	99 participants	101 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=229, 228	2 participants	5 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=177, 180	2 participants	6 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	6 participants	5 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=229, 228	7 participants	8 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=177, 180	8 participants	1 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	3 participants	1 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=229, 228	1 participants	1 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=177, 180	2 participants	1 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Month 1, Grade 4, n=177, 180	0 participants	1 participants
Number of Participants With the Indicated Investigator Assessment for the Neurological Sign and Symptom of Other Neurological Symptoms at Baseline, Month 1, and Month 3 Month 3, Grade 5, n=109, 107	1 participants	0 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants' status of cranial nerves II-XII and assigned each participant to one of the following categories: normal; present, not interfering with ADLs; present, interfering with ADLs; life threatening, disabling.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=229 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=225 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment of Cranial Nerves II-XII at Baseline, Month 1, and Month 3 Baseline, normal, n=229, 225	218 participants	211 participants
Number of Participants With the Indicated Investigator Assessment of Cranial Nerves II-XII at Baseline, Month 1, and Month 3 Month 1, normal, n=177, 179	172 participants	169 participants
Number of Participants With the Indicated Investigator Assessment of Cranial Nerves II-XII at Baseline, Month 1, and Month 3 Month 3, normal, n=109, 107	106 participants	102 participants
Number of Participants With the Indicated Investigator Assessment of Cranial Nerves II-XII at Baseline, Month 1, and Month 3 Baseline, present, not interfering, n=229, 225	11 participants	10 participants
Number of Participants With the Indicated Investigator Assessment of Cranial Nerves II-XII at Baseline, Month 1, and Month 3 Month 1, present, not interfering, n=177, 179	4 participants	6 participants
Number of Participants With the Indicated Investigator Assessment of Cranial Nerves II-XII at Baseline, Month 1, and Month 3 Month 3, present, not interfering, n=109, 107	3 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Cranial Nerves II-XII at Baseline, Month 1, and Month 3 Baseline, present, interfering, n=229, 225	0 participants	4 participants
Number of Participants With the Indicated Investigator Assessment of Cranial Nerves II-XII at Baseline, Month 1, and Month 3 Month 1, present, interfering, n=177, 179	1 participants	4 participants
Number of Participants With the Indicated Investigator Assessment of Cranial Nerves II-XII at Baseline, Month 1, and Month 3 Month 3, present, interfering, n=109, 107	0 participants	3 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants' status of language (dysphasia or aphasia) and assigned each participant to one of the following categories: absent; awareness of receptive or expressive aphasia, not impairing ability to communicate (not impaired); receptive or expressive dysphasia, impairing ability to communicate (impaired); inability to communicate (unable).

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment of Language (Dysphasia or Aphasia) at Baseline, Month 1, and Month 3 Baseline, absent, n=230, 228	211 participants	215 participants
Number of Participants With the Indicated Investigator Assessment of Language (Dysphasia or Aphasia) at Baseline, Month 1, and Month 3 Month 1, absent, n=178, 180	169 participants	173 participants
Number of Participants With the Indicated Investigator Assessment of Language (Dysphasia or Aphasia) at Baseline, Month 1, and Month 3 Month 3, absent, n=109, 107	105 participants	98 participants
Number of Participants With the Indicated Investigator Assessment of Language (Dysphasia or Aphasia) at Baseline, Month 1, and Month 3 Baseline, not impaired, n=230, 228	15 participants	10 participants
Number of Participants With the Indicated Investigator Assessment of Language (Dysphasia or Aphasia) at Baseline, Month 1, and Month 3 Month 1, not impaired, n=178, 180	6 participants	5 participants
Number of Participants With the Indicated Investigator Assessment of Language (Dysphasia or Aphasia) at Baseline, Month 1, and Month 3 Month 3, not impaired, n=109, 107	3 participants	7 participants
Number of Participants With the Indicated Investigator Assessment of Language (Dysphasia or Aphasia) at Baseline, Month 1, and Month 3 Baseline, impaired, n=230, 228	3 participants	3 participants
Number of Participants With the Indicated Investigator Assessment of Language (Dysphasia or Aphasia) at Baseline, Month 1, and Month 3 Month 1, impaired, n=178, 180	3 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Language (Dysphasia or Aphasia) at Baseline, Month 1, and Month 3 Month 3, impaired, n=109, 107	1 participants	0 participants
Number of Participants With the Indicated Investigator Assessment of Language (Dysphasia or Aphasia) at Baseline, Month 1, and Month 3 Baseline, unable, n=230, 228	1 participants	0 participants
Number of Participants With the Indicated Investigator Assessment of Language (Dysphasia or Aphasia) at Baseline, Month 1, and Month 3 Month 3, unable, n=109, 107	0 participants	2 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants' status of strength (right upper extremity) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic with weakness on physical examination; Grade 2, symptomatic and interfering with function, but not interfering with ADLs; Grade 3, symptomatic and interfering with ADLs; Grade 4: bedridden or disabling.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 179	4 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 3, n=109, 107	2 participants	3 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 4, n=230, 228	1 participants	0 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 4, n=178, 179	2 participants	1 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Baseline, normal, n=230, 228	203 participants	195 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Month 1, normal, n=178, 179	153 participants	159 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Month 3, normal, n=109, 107	93 participants	89 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 228	15 participants	16 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 179	13 participants	12 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	10 participants	10 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 228	6 participants	12 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 179	6 participants	5 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	4 participants	5 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Upper Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 228	5 participants	5 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants' status of strength (left upper extremity) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic with weakness on physical examination; Grade 2, symptomatic and interfering with function, but not interfering with ADLs; Grade 3, symptomatic and interfering with ADLs; Grade 4: bedridden or disabling.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 228	16 participants	13 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 179	16 participants	13 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	10 participants	11 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 228	11 participants	8 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 179	8 participants	5 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	6 participants	5 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 228	6 participants	4 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Month 1, normal, n=178, 179	149 participants	157 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Month 3, normal, n=109, 107	90 participants	86 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 179	3 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 3, n=109, 107	3 participants	4 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 4, n=230, 228	0 participants	1 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 4, n=178, 179	2 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 4, n=109, 107	0 participants	1 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Upper Extremity) at Baseline, Month 1, and Month 3 Baseline, normal, n=230, 228	197 participants	202 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants' status of strength (right lower extremity) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic with weakness on physical examination; Grade 2, symptomatic and interfering with function, but not interfering with ADLs; Grade 3, symptomatic and interfering with ADLs; Grade 4: bedridden or disabling.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Baseline, normal, n=230, 228	196 participants	189 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Month 1, normal, n=178, 180	137 participants	145 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Month 3, normal, n=109, 107	81 participants	80 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 228	20 participants	19 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 180	17 participants	15 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	12 participants	11 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 228	9 participants	16 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 228	3 participants	4 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 180	9 participants	0 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 3, n=109, 107	4 participants	3 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 180	11 participants	19 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	11 participants	11 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 4, n=230, 228	2 participants	0 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 4, n=178, 180	4 participants	1 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Right Lower Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 4, n=109, 107	1 participants	2 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants' status of strength (left lower extremity) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic with weakness on physical examination; Grade 2, symptomatic and interfering with function, but not interfering with ADLs; Grade 3, symptomatic and interfering with ADLs; Grade 4: bedridden or disabling.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Month 1, normal, n=178, 179	128 participants	143 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Month 3, normal, n=109, 107	76 participants	73 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	11 participants	11 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 228	15 participants	15 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 179	11 participants	17 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 228	28 participants	18 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 179	26 participants	13 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 179	10 participants	4 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 3, n=109, 107	6 participants	5 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 4, n=230, 228	1 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Month 1, Grade 4, n=178, 179	3 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 4, n=109, 107	2 participants	4 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	14 participants	14 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 228	4 participants	3 participants
Number of Participants With the Indicated Investigator Assessment of Strength (Left Lower Extremity) at Baseline, Month 1, and Month 3 Baseline, normal, n=230, 228	182 participants	190 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants' status of sensation and assigned each participant to one of the following categories: normal; loss of deep tendon reflexes or paresthesia, but not interfering with function (not interfering with function); objective sensory loss or paresthesia interfering with function, but not interfering with ADLs (interfering with function); sensory loss or paresthesia interfering with ADLs (intefering with ADLs); permanent sensory loss that interferes with function (permanent sensory loss).

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 Baseline (BL), normal, n=230, 228	197 participants	192 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 Month (M) 1, normal, n=178, 180	144 participants	159 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 Month 3, normal, n=109, 107	100 participants	94 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 BL, not interfering with function, n=230, 228	26 participants	26 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 M 1, not interfering with function, n=178, 180	22 participants	15 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 M 3, not interfering with function, n=109, 107	5 participants	9 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 BL, interfering with function, n=230, 228	3 participants	6 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 M 1, interfering with function, n=178, 180	7 participants	4 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 M 3, interfering with function, n=109, 107	2 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 Baseline, interfering with ADLs, n=230, 228	4 participants	3 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 Month 1, interfering with ADLs, n=178, 180	5 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 Month 3, interfering with ADLs, n=109, 107	2 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Sensation at Baseline, Month 1, and Month 3 Baseline, permanent sensory loss, n=230, 228	0 participants	1 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants' status of ataxia (right upper extremity: finger to nose testing) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic but abnormal on physical examination, and not interfering with function; Grade 2, mild symptoms interfering with function, but not interfering with ADLs; Grade 3, moderate symptoms interfering with ADLs; Grade 4, bedridden or disabling.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=229 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Baseline, Grade 4, n=229, 228	2 participants	0 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 1, Grade 4, 178, 179	2 participants	1 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 3, Grade 4, n=109, 107	0 participants	1 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Baseline, normal, n=229, 228	206 participants	198 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 1, normal, 178, 179	166 participants	166 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 3, normal, n=109, 107	103 participants	95 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=229, 228	13 participants	17 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 1, Grade 1, 178, 179	7 participants	6 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	6 participants	5 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=229, 228	5 participants	12 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 1, Grade 2, 178, 179	3 participants	6 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	0 participants	5 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=229, 228	3 participants	1 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Right Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 3, Grade 3, n=109, 107	0 participants	1 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants' status of ataxia (left upper extremity: finger to nose testing) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic but abnormal on physical examination, and not interfering with function; Grade 2, mild symptoms interfering with function, but not interfering with ADLs; Grade 3, moderate symptoms interfering with ADLs; Grade 4, bedridden or disabling.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=227 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Baseline, normal, n=230, 227	199 participants	201 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 1, normal, n=178, 178	156 participants	162 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 3, normal, n=109, 107	97 participants	94 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 227	15 participants	13 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 178	14 participants	9 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=109, 107	10 participants	6 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 227	8 participants	7 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 178	6 participants	3 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=109, 107	2 participants	3 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 227	8 participants	4 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 178	0 participants	3 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 3, Grade 3, n=109, 107	0 participants	1 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Baseline, Grade 4, n=230, 227	0 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 1, Grade 4, n=178, 178	2 participants	1 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Left Upper Extremity: Finger to Nose Testing) at Baseline, Month 1, and Month 3 Month 3, Grade 4, n=109, 107	0 participants	3 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants' status of ataxia (gait) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic but abnormal on physical examination, and not interfering with function; Grade 2, mild symptoms interfering with function, but not interfering with ADLs; Grade 3, moderate symptoms interfering with ADLs; Grade 4, bedridden or disabling.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=227 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Baseline, normal, n=230, 227	172 participants	178 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Month 1, normal, n=178, 179	138 participants	147 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Month 3, normal, n=108, 107	85 participants	76 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 227	13 participants	22 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 179	16 participants	13 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=108, 107	9 participants	10 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 227	37 participants	20 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 179	14 participants	14 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=108, 107	9 participants	12 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 227	6 participants	6 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 179	7 participants	3 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Month 3, Grade 3, n=108, 107	4 participants	5 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Baseline, Grade 4, n=230, 227	2 participants	1 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Month 1, Grade 4, n=178, 179	3 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Gait) at Baseline, Month 1, and Month 3 Month 3, Grade 4, n=108, 107	1 participants	4 participants

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Population: ITT Population. Only those participants who were assessed at the indicated time point were analyzed. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

The investigator assessed participants' status of ataxia (balance) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic but abnormal on physical examination, and not interfering with function; Grade 2, mild symptoms interfering with function, but not interfering with ADLs; Grade 3, moderate symptoms interfering with ADLs; Grade 4, bedridden or disabling.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=230 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=228 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Baseline, normal, n=230, 228	153 participants	152 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Month 1, normal, n=178, 178	131 participants	128 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Month 3, normal, n=108, 107	78 participants	75 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Baseline, Grade 1, n=230, 228	37 participants	44 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Month 1, Grade 1, n=178, 178	23 participants	28 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Month 3, Grade 1, n=108, 107	17 participants	13 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Baseline, Grade 2, n=230, 228	27 participants	23 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Month 1, Grade 2, n=178, 178	13 participants	16 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Month 3, Grade 2, n=108, 107	8 participants	9 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Baseline, Grade 3, n=230, 228	10 participants	7 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Month 1, Grade 3, n=178, 178	8 participants	5 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Month 3, Grade 3, n=108, 107	4 participants	5 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Baseline, Grade 4, n=230, 228	3 participants	2 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Month 1, Grade 4, n=178, 178	3 participants	1 participants
Number of Participants With the Indicated Investigator Assessment of Ataxia (Balance) at Baseline, Month 1, and Month 3 Month 3, Grade 4, n=108, 107	1 participants	5 participants

SECONDARY outcome

Timeframe: From Randomization until the last clinic visit associated with the study, up until 35 days after the start of the last course of treatment (up to 75 weeks)

Population: Modified ITT Population: all randomized participants who received at least one dose of randomized therapy. Participants were analyzed by the actual treatment received, even if this differed from the treatment to which they were randomized.

An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect. For a list of all SAEs and AEs, see the SAE/AE module of this results summary.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=235 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=233 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With Any Adverse Event (AE; Both Serious and Non-serious) or Serious Adverse Event (SAE) AE	204 participants	148 participants
Number of Participants With Any Adverse Event (AE; Both Serious and Non-serious) or Serious Adverse Event (SAE) SAE	96 participants	43 participants

SECONDARY outcome

Timeframe: From Randomization until the last clinic visit associated with the study, up until 35 days after the start of the last course of treatment (up to 75 weeks)

Population: Modified ITT Population. Only those participants with available laboratory values (indicated by the "n" in the category titles) were analyzed. Different participants may have been analyzed for different parameters; therefore, the overall number of participants analyzed reflects everyone in the Modified ITT Population.

The worst-case change from Baseline in chemistry parameters was measured as decrease to low (DTL), change to normal or no change (CTN/NC), or increase to high (ITH). The worst-case change value could have been measured at any point during the on-therapy period. Participants are counted twice if the participant "Decreased to Low" and "Increased to High" during the on-therapy period.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=235 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=233 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Chloride, DTL, n=169, 171	32 participants	21 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Chloride, CTN/NC, n=169, 171	116 participants	144 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Chloride, ITH, n=169, 171	22 participants	6 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Creatinine clearance, DTL, n=159, 145	26 participants	9 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Creatinine clearance, CTN/NC, n=159, 145	121 participants	134 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Creatinine clearance, ITH, n=159, 145	15 participants	2 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Lactate dehydrogenase, DTL, n=169, 168	8 participants	1 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Lactate dehydrogenase, CTN/NC, n=169, 168	117 participants	127 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Lactate dehydrogenase, ITH, n=169, 168	47 participants	40 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Total protein, DTL, n=171, 175	48 participants	36 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Total protein, CTN/NC, n=171, 175	119 participants	137 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Total protein, ITH, n=171, 175	4 participants	2 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Urea/blood urea nitrogen, DTL, n=178, 179	7 participants	4 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Urea/blood urea nitrogen, CTN/NC, n=178, 179	139 participants	152 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Urea/blood urea nitrogen, ITH, n=178, 179	33 participants	24 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Uric acid, DTL, n=159, 152	21 participants	12 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Uric acid, CTN/NC, n=159, 152	125 participants	134 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Uric acid, ITH, n=159, 152	13 participants	6 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Basophils, DTL, n=215, 211	7 participants	1 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Basophils, CTN/NC, n=215, 211	186 participants	200 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Basophils, ITH, n=215, 211	25 participants	10 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Eosinophils, DTL, n=214, 211	28 participants	12 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Eosinophils, CTN/NC, n=214, 211	182 participants	191 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Eosinophils, ITH, n=214, 211	4 participants	8 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Hematocrit, DTL, n=215, 212	98 participants	38 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Hematocrit, CTN/NC, n=215, 212	117 participants	169 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Hematocrit, ITH, n=215, 212	1 participants	6 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Monocytes, DTL, n=216, 212	84 participants	17 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Monocytes, CTN/NC, n=216, 212	119 participants	161 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Monocytes, ITH, n=216, 212	54 participants	37 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Red Blood Cell Count, DTL, n=216, 212	103 participants	38 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Red Blood Cell Count, CTN/NC, n=216, 212	113 participants	171 participants
Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Chemistry Parameters With Respect to the Normal Range Red Blood Cell Count, ITH, n=216, 212	0 participants	4 participants

SECONDARY outcome

Timeframe: From the time of Randomization until the time of CR or PR (up to 75 weeks)

Lesions were assessed per WHO criteria. For lesion assessment data, see the outcome measure entitled "Number of participants with a complete response (CR) or a partial response (PR) (central nervous system [CNS]-radiologic)."

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, Month 1, and Month 3

Brain symptoms were assessed as the number of participants with neurological signs and symptoms. For brain symptom data, see the outcome measures entitled "Number of participants with the indicated investigator assessment for the neurological sign and symptom of X at Baseline, Month 1, and Month 3."

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Randomization until the last clinic visit associated with the study, up until 35 days after the start of the last course of treatment (up to 75 weeks)

Population: mITT Population

Disease-related events were measured as the number of participants who died or progressed. Progressive disease (PD) is defined as an increase >=25% in any measurable lesion or, in participants with non-measurable disease only, an estimation of an increase >=25%. In both cases, determination of progression included the appearance of any new lesions, or signification worsening of conditions presumed to be related to malignancy. Participants with clinical or laboratory evidence of possible disease progression were to be evaluated radiologically. Data were analyzed with censoring for extended loss to follow-up to account for two or more missed assessments before an event. The date of the last adequate CNS assessment before extended loss to follow-up was used for censored participants.

Outcome measures

Measure	Chemoradiation: Topotecan Plus WBRT n=235 Participants Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=233 Participants Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Number of Participants Who Died or Progressed	179 participants	161 participants

Adverse Events

Chemoradiation: Topotecan Plus WBRT

Serious events: 96 serious events

Other events: 192 other events

Deaths: 0 deaths

Radiation: WBRT Alone

Serious events: 43 serious events

Other events: 139 other events

Deaths: 0 deaths

Serious adverse events

Measure	Chemoradiation: Topotecan Plus WBRT n=235 participants at risk Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=233 participants at risk Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Blood and lymphatic system disorders Neutropenia	9.4% 22/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Thrombocytopenia	9.4% 22/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Anaemia	6.8% 16/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Febrile neutropenia	5.5% 13/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Pneumonia	3.0% 7/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	2.6% 6/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Leukopenia	3.4% 8/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Dehydration	2.1% 5/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Asthenia	2.1% 5/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Diarrhoea	2.6% 6/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Pancytopenia	2.6% 6/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Pyrexia	2.1% 5/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.7% 4/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Sepsis	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Deep vein thrombosis	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Dyspnoea	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Brain oedema	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Disease progression	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Nausea	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Septic shock	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Vomiting	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Accidental overdose	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Atrial fibrillation	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Cardiac failure acute	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Cerebrovascular accident	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Confusional state	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Constipation	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Hyperglycaemia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Muscular weakness	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Overdose	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Performance status decreased	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Pericarditis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Small intestinal haemorrhage	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Syncope	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Acute myocardial infarction	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Endocrine disorders Adrenal insufficiency	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Agranulocytosis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Arterial thrombosis limb	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Aspiration	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood bilirubin increased	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood creatinine increased	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Bronchial obstruction	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Bronchitis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Cardiopulmonary failure	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Cellulitis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Convulsion	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Coronary artery insufficiency	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Decreased appetite	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Diabetes mellitus	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Encephalopathy	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Face injury	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Fatigue	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Femur fracture	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders General physical health deterioration	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Grand mal convulsion	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Haematuria	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Headache	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Herpes zoster	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Hydrocephalus	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Hypernatraemia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Hyponatraemia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Endocrine disorders Inappropriate antidiuretic hormone secretion	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Intestinal perforation	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Jugular vein thrombosis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Lobar pneumonia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Lower respiratory tract infection	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Lung abscess	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Lung infiltration	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Lymphopenia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Malnutrition	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Mental status changes	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Myocardial infarction	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Myocardial ischaemia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Non-cardiac chest pain	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Oedema peripheral	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Oesophageal stenosis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Oropharyngeal pain	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Oropharyngitis fungal	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Orthostatic hypotension	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Pain	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Pancreatitis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Paraplegia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Peridiverticular abscess	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pleurisy	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Radiation pneumonitis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Radiculopathy	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Renal failure	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Stevens-Johnson syndrome	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Superior vena cava syndrome	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Upper respiratory tract infection	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Urinary retention	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Venous thrombosis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Weight decreased	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.

Other adverse events

Measure	Chemoradiation: Topotecan Plus WBRT n=235 participants at risk Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.	Radiation: WBRT Alone n=233 participants at risk Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.
Gastrointestinal disorders Nausea	27.2% 64/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	12.9% 30/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Vomiting	15.7% 37/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	10.3% 24/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Diarrhoea	8.1% 19/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	3.4% 8/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Dyspepsia	7.2% 17/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	4.3% 10/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Constipation	3.4% 8/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	4.3% 10/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Abdominal pain	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	2.6% 6/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Stomatitis	3.0% 7/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Abdominal pain upper	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Dysphagia	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Dry mouth	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Gastrooesophageal reflux disease	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Abdominal distension	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Flatulence	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Mouth ulceration	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Rectal haemorrhage	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Abdominal discomfort	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Aphthous stomatitis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Ascites	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Breath odour	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Faecal incontinence	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Faeces discoloured	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Gastritis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Gingival pain	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Glossodynia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Haematochezia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Haemorrhoids	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Hyperchlorhydria	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Oesophageal pain	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Oral pain	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Gastrointestinal disorders Retching	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Fatigue	16.6% 39/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	15.9% 37/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Asthenia	12.3% 29/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	8.2% 19/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Oedema peripheral	6.4% 15/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	6.4% 15/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Pyrexia	5.5% 13/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	2.1% 5/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Mucosal inflammation	3.0% 7/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Gait disturbance	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.7% 4/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Face oedema	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Pain	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Chest pain	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Chills	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Non-cardiac chest pain	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Spinal pain	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Chest discomfort	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Early satiety	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Gravitational oedema	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Hyperthermia	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Influenza like illness	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Local swelling	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Localised oedema	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Malaise	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Mucosal erosion	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Oedema	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
General disorders Swelling	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Headache	11.5% 27/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	12.0% 28/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Dizziness	11.5% 27/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	8.2% 19/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Somnolence	6.0% 14/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	6.0% 14/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Hypoaesthesia	2.6% 6/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	4.7% 11/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Ataxia	3.4% 8/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	2.6% 6/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Coordination abnormal	3.0% 7/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.7% 4/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Tremor	2.6% 6/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.7% 4/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Paraesthesia	2.1% 5/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.7% 4/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Amnesia	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	2.6% 6/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Dysgeusia	2.6% 6/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Aphasia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	2.6% 6/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Balance disorder	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	3.0% 7/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Convulsion	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Epilepsy	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Neuropathy peripheral	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Peripheral sensory neuropathy	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Speech disorder	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Syncope	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Brain oedema	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Convulsions local	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Hemiparesis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Hemiplegia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Loss of consciousness	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Memory impairment	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Psychomotor hyperactivity	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Ageusia	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Alcoholic seizure	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Burning sensation	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Cognitive disorder	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Dysarthria	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Facial paresis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Hypersomnia	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Hypotonia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Mental impairment	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Monoplegia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Neuritis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Paresis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Partial seizures	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Peripheral motor neuropathy	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Polyneuropathy	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Sciatica	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Nervous system disorders Visual field defect	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Dyspnoea	13.2% 31/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	8.6% 20/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Cough	11.1% 26/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	7.3% 17/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Epistaxis	3.4% 8/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Haemoptysis	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	3.0% 7/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.1% 5/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Hiccups	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Productive cough	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Dysphonia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Lung infiltration	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Upper-airway cough syndrome	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Wheezing	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Bronchitis chronic	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Hydrothorax	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Increased upper airway secretion	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Laryngeal inflammation	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pharyngeal inflammation	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Rales	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Respiratory tract congestion	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Muscular weakness	12.3% 29/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	9.4% 22/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Pain in extremity	3.4% 8/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	2.6% 6/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Arthralgia	2.6% 6/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	2.6% 6/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Back pain	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.7% 4/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Muscle spasms	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Myalgia	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Joint swelling	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Neck pain	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Bone pain	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Extremity contracture	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Groin pain	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Muscle atrophy	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Decreased appetite	11.9% 28/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	7.3% 17/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Increased appetite	3.0% 7/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	2.6% 6/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Hypokalaemia	3.8% 9/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Hyperglycaemia	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Dehydration	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.7% 4/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Hyponatraemia	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Cachexia	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Hypoalbuminaemia	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Hypomagnesaemia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Hypocalcaemia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Hyperkalaemia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Malnutrition	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Metabolism and nutrition disorders Polydipsia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Pneumonia	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.7% 4/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Oral candidiasis	2.1% 5/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Urinary tract infection	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.7% 4/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Candidiasis	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Oral fungal infection	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Oropharyngitis fungal	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Upper respiratory tract infection	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Nasopharyngitis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Rhinitis	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Bronchitis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Cystitis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Herpes zoster	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Influenza	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Oesophageal candidiasis	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Oral herpes	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Oropharyngeal candidiasis	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Pharyngitis	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Anal fungal infection	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Fungal infection	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Fungal oesophagitis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Furuncle	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Herpes simplex	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Infection	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Mastoiditis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Orchitis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Otitis media	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Rash pustular	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Respiratory tract infection	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Soft tissue infection	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Tonsillitis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Tracheobronchitis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Vaginal infection	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Infections and infestations Vulvovaginal mycotic infection	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Insomnia	7.2% 17/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	8.2% 19/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Confusional state	3.0% 7/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	4.7% 11/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Anxiety	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Depression	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Mood altered	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Nervousness	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Delusion	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Depressed mood	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Disorientation	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Initial insomnia	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Mental disorder	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Sleep disorder	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Psychiatric disorders Staring	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Alopecia	8.9% 21/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	7.3% 17/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Erythema	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Pruritus	2.1% 5/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Rash	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Dry skin	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Swelling face	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Acne	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Ecchymosis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Night sweats	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Skin disorder	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Skin ulcer	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Dermatitis allergic	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Haemorrhage subcutaneous	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Increased tendency to bruise	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Petechiae	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Rash papular	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Skin and subcutaneous tissue disorders Skin exfoliation	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Weight decreased	7.7% 18/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	3.4% 8/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood lactate dehydrogenase increased	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Platelet count decreased	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Haemoglobin decreased	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Alanine aminotransferase increased	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Weight increased	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood glucose increased	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Neutrophil count decreased	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations White blood cell count decreased	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Aspartate aminotransferase increased	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Bacterial test positive	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood alkaline phosphatase increased	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood bilirubin increased	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood creatinine increased	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood magnesium increased	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood phosphorus decreased	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood phosphorus increased	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood urea increased	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Blood uric acid increased	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Body temperature increased	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Breath sounds abnormal	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations Gamma-glutamyltransferase increased	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Investigations International normalised ratio increased	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Eye disorders Vision blurred	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	3.4% 8/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Eye disorders Visual acuity reduced	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Eye disorders Visual impairment	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Eye disorders Asthenopia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Eye disorders Blindness	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Eye disorders Conjunctivitis	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Eye disorders Eye inflammation	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Eye disorders Eye pain	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Eye disorders Myopia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Eye disorders Retinal vascular disorder	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Ear and labyrinth disorders Vertigo	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Ear and labyrinth disorders Tinnitus	1.7% 4/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Ear and labyrinth disorders Ear pain	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Ear and labyrinth disorders Ear pruritus	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Ear and labyrinth disorders Auricular swelling	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Ear and labyrinth disorders Deafness	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Ear and labyrinth disorders Hearing impaired	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Ear and labyrinth disorders Hypoacusis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Hypotension	2.6% 6/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Deep vein thrombosis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Hypertension	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Flushing	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Phlebitis	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Haematoma	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Hot flush	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Orthostatic hypotension	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Vascular disorders Thrombophlebitis superficial	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Anaemia	3.0% 7/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Thrombocytopenia	2.1% 5/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Neutropenia	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Leukopenia	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Coagulopathy	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Febrile neutropenia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Blood and lymphatic system disorders Pancytopenia	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Atrial fibrillation	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.86% 2/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Tachycardia	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Cardiac failure	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Palpitations	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Angina pectoris	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Cardiac failure congestive	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Sinus tachycardia	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Cardiac disorders Supraventricular extrasystoles	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Haematuria	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Dysuria	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Pollakiuria	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Chromaturia	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Incontinence	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Nephrolithiasis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Proteinuria	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Urinary bladder haemorrhage	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Urinary incontinence	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Renal and urinary disorders Urinary retention	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	1.3% 3/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	1.3% 3/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.85% 2/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to skin	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Fall	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Thermal burn	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Contusion	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Incision site pain	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Overdose	0.00% 0/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Radiation skin injury	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Injury, poisoning and procedural complications Skin wound	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Endocrine disorders Cushingoid	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.43% 1/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Endocrine disorders Inappropriate antidiuretic hormone secretion	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Reproductive system and breast disorders Epididymitis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Reproductive system and breast disorders Prostatitis	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.
Hepatobiliary disorders Hepatic function abnormal	0.43% 1/235 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.	0.00% 0/233 Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

• Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
• Publication restrictions are in place

Restriction type: OTHER