Trial Outcomes & Findings for Efficacy and Safety of Pazopanib Monotherapy After First-line Chemotherapy in Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Asian Women (NCT NCT01227928)

NCT ID: NCT01227928

Last Updated: 2015-03-03

Results Overview

PFS is defined as the time interval between randomization and evidence of progressive disease (PD), as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, or death, whichever occurred first. A visit-based analysis approach to determine participants' dates of progression was applied in the analysis method. PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Participants who were alive and had not progressed at the time of analysis were censored at the date associated with the last visit with adequate assessment.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 145 participants
• Primary outcome timeframe: From randomization until evidence of progressive disease or death, whichever occurred first (average of 15.2 months)
• Results posted on: 2015-03-03

Participant Flow

Participant milestones

Measure	Placebo Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Overall Study STARTED	72	73
Overall Study COMPLETED	50	56
Overall Study NOT COMPLETED	22	17

Reasons for withdrawal

Measure	Placebo Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Overall Study Lost to Follow-up	4	2
Overall Study Withdrawal by Subject	4	3
Overall Study Death	14	12

Baseline Characteristics

Efficacy and Safety of Pazopanib Monotherapy After First-line Chemotherapy in Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Asian Women

Baseline characteristics by cohort

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=73 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.	Total n=145 Participants Total of all reporting groups
Age, Continuous	54.1 Years STANDARD_DEVIATION 10.46 • n=5 Participants	51.7 Years STANDARD_DEVIATION 9.62 • n=7 Participants	52.9 Years STANDARD_DEVIATION 10.09 • n=5 Participants
Sex: Female, Male Female	72 Participants n=5 Participants	73 Participants n=7 Participants	145 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	72 participants n=5 Participants	73 participants n=7 Participants	145 participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization until evidence of progressive disease or death, whichever occurred first (average of 15.2 months)

Population: Intent-to-Treat (ITT) Population: all randomized participants who were not screen failures. Participants who were screen failures and randomized by mistake, but who did not receive study treatment, were not included. The treatment assignment in the ITT Population was based on the randomized treatment. The data cut off was October 12, 2012.

PFS is defined as the time interval between randomization and evidence of progressive disease (PD), as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, or death, whichever occurred first. A visit-based analysis approach to determine participants' dates of progression was applied in the analysis method. PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Participants who were alive and had not progressed at the time of analysis were censored at the date associated with the last visit with adequate assessment.

Outcome measures

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=73 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Progression-free Survival (PFS)	18.1 months Interval 12.1 to The lower and upper bounds of the confidence intervals were calculated when there was a sufficient number of events (progressions or deaths).	18.1 months Interval 18.0 to 18.1

SECONDARY outcome

Timeframe: From randomization until death due to any cause (average of 29.4 months)

Population: ITT Population. Participants who were alive as of study completion were censored at the last contact date. The cut off for these data was January 10, 2014.

Overall survival is defined as the time interval from the date of randomization to the date of death due to any cause.

Outcome measures

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=73 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Overall Survival	NA months There were too few events of death for median overall survival or the 95% confidence interval to be reached.	NA months There were too few events of death for median overall survival or the 95% confidence interval to be reached.

SECONDARY outcome

Timeframe: From randomization to the earliest date of disease progression per GCIG criteria or death due to any cause (average of 15.2 months)

Population: ITT Population. The cut off for these data was October 12, 2012.

PFS by GCIG criteria is defined as the time from the randomization date to the earliest date of disease progression (PD) per GCIG criteria or death due to any cause. Per GCIG criteria, an objective progression is defined as the earliest event of either tumor progression based on RECIST v1.0 or confirmed CA-125 progression. A participant is counted as "Progressed per RECIST" if the radiological PD per RECIST occurred prior to or on the same day as CA-125 progression. A participant is counted as "Progressed per CA-125" if the radiological PD occurred after CA-125 progression. Per RECIST, PD is defined as at least a 20% increase in the sum of the LD of target lesions, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Participants who were alive and had not progressed at the time of analysis were censored at the date associated with the last visit with adequate assessment.

Outcome measures

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=73 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
PFS by Gynaecologic Cancer Intergroup (GCIG) Criteria	15.2 months Interval 9.0 to The lower and upper bounds of the confidence intervals were calculated when there was a sufficient number of events (progressions or deaths).	16.1 months Interval 14.2 to 18.2

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population: all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.

Dose interruptions or reductions may have been required following potential drug-related toxicities. As a general rule, if dose reduction of investigational product (IP) was necessary, the dose should have been reduced stepwise by 200 mg at each step, and the participant should have been monitored for 10 to 14 days. If toxicity recurred or worsened during this monitoring time, the IP could have been interrupted and/or the dose of IP further decreased, with continued monitoring for an additional 10 to 14 days, and so on. The cut off for these data was October 12, 2012.

Outcome measures

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=72 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With Any Dose Reduction or Any Dose Interruption Any Interruption	44 participants	65 participants
Number of Participants With Any Dose Reduction or Any Dose Interruption Any Reduction	26 participants	64 participants

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population: all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment. The cut off for these data was January 10, 2014.

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalizaton or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. See the non-serious AE/SAE module for a list of specific events.

Outcome measures

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=72 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With Any Non-serious Adverse Event (AE) and Any Serious Adverse Event (SAE) Any AE	65 participants	72 participants
Number of Participants With Any Non-serious Adverse Event (AE) and Any Serious Adverse Event (SAE) Any SAE	4 participants	7 participants

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population: all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment. The cut off for these data was January 10, 2014.

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. On-therapy AEs were those reported from the first day that randomized study drug was received to 28 days after the last dose of randomized study drug, and within 28 days of dose interruption. Relatedness was assessed by the Investigator.

Outcome measures

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=72 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With Any On-therapy AE and Any AE Related to Study Treatment Any on-therapy AE	65 participants	72 participants
Number of Participants With Any On-therapy AE and Any AE Related to Study Treatment Any AE related to study treatment	52 participants	71 participants

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population: all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment. The cut off for these data was January 10, 2014.

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. The NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 3.0 was used to grade AEs per the following scale to assess severity: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling AE; Grade 5, death related to AE.

Outcome measures

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=72 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With Any Grade 3 or 4 AE	8 participants	39 participants

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population: all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment. The cut off for these data was January 10, 2014.

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. On-therapy AEs were those reported from the first day that randomized study drug was received to 28 days after the last dose of randomized study drug, and within 28 days of dose interruption. The NCI-CTCAE Version 3.0 was used to grade AEs per the following scale to assess severity: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling AE; Grade 5, death related to AE. ALT=alanine aminotransferase; AST=aspartate aminotransferase.

Outcome measures

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=72 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Bradycardia, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Febrile neutropenia, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Protein urine, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Proteinuria, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Bone pain, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Diarrhea, Grade 3	1 participants	5 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs ALT increased, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Thrombocytopenia, Grade 3	0 participants	3 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs AST increased, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Neutrophil count decreased, Grade 3	0 participants	2 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Toothache, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Pyrexia, Grade 3	1 participants	0 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Hepatic function abnormal, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Liver injury, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Thrombus in device, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Abdominal distension, Grade 3	1 participants	0 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Leukopenia, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Pruritis, Grade 3	1 participants	0 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Amylase increased, Grade 3	1 participants	0 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Cerebral ischaemia, Grade 3	1 participants	0 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Foot fracture, Grade 3	1 participants	0 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Hypertension, Grade 3	1 participants	13 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Neutropenia, Grade 3	0 participants	9 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Neutrophil count decreased, Grade 4	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Arthralgia, Grade 3	0 participants	1 participants
Number of Participants With the Indicated On-therapy Grade 3-5 AEs Upper respiratory tract infection, Grade 3	1 participants	0 participants

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population: all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment. The cut off for these data was January 10, 2014.

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. Dose interruptions or reductions may have been required following potential drug-related toxicities. As a general rule, if dose reduction of investigational product (IP) was necessary, the dose should have been reduced stepwise by 200 mg at each step, and the participant should have been monitored for 10 to 14 days. If toxicity recurred or worsened during this monitoring time, the IP could have been interrupted and/or the dose of IP further decreased, with continued monitoring for an additional 10 to 14 days, and so on.

Outcome measures

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=72 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment, Dose Interruption, and Dose Reduction Permanent discontinuation	1 participants	18 participants
Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment, Dose Interruption, and Dose Reduction Dose reduction	24 participants	63 participants
Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment, Dose Interruption, and Dose Reduction Dose interruption	29 participants	67 participants

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population: all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment. The cut off for these data was January 10, 2014.

An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalizaton or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. See the non-serious AE/SAE module for a list of specific events. Relatedness was assessed by the Investigator.

Outcome measures

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=72 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With Any SAE, Any SAE Related to Study Treatment, and Any Fatal SAE Any SAE	4 participants	7 participants
Number of Participants With Any SAE, Any SAE Related to Study Treatment, and Any Fatal SAE Any SAE related to study treatment	1 participants	4 participants
Number of Participants With Any SAE, Any SAE Related to Study Treatment, and Any Fatal SAE Any fatal SAE	0 participants	0 participants

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population. One participant on placebo did not report any blood pressure measurements post-Baseline. The cut off for these data was January 10, 2014.

Systolic blood pressure (SBP) and Diatolic blood pressure (DBP) are measured in millimeters of mercury (mmHg). A participant could have been counted in more than one shift category. Participants who experienced shifts in both SBP and DBP are represented under each individual parameter. A worst-case on-therapy shift is defined as the worst shift that occurred at any time during the treatment period.

Outcome measures

Measure	Placebo n=71 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=72 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With the Indicated Worst-case On-therapy Blood Pressure Shifts From Baseline SBP, Any increase to >=120 mmHg	28 participants	53 participants
Number of Participants With the Indicated Worst-case On-therapy Blood Pressure Shifts From Baseline SBP, Increase to 140-<160 mmHg	4 participants	23 participants
Number of Participants With the Indicated Worst-case On-therapy Blood Pressure Shifts From Baseline SBP, Increase to >=160 mmHg	0 participants	6 participants
Number of Participants With the Indicated Worst-case On-therapy Blood Pressure Shifts From Baseline DBP, Any increase to >=80 mmHg	35 participants	59 participants
Number of Participants With the Indicated Worst-case On-therapy Blood Pressure Shifts From Baseline DBP, Increase to 90-<100 mmHg	1 participants	25 participants
Number of Participants With the Indicated Worst-case On-therapy Blood Pressure Shifts From Baseline DBP, Increase to >=100 mmHg	0 participants	5 participants

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population. Only those participants for which a post-Baseline ECG was conducted were analyzed. The cut off for these data was October 12, 2012.

12-lead ECGs were obtained at the scheduled visits. A worst-case on-therapy shift is defined as the worst shift that occurred at any time during the treatment period. The QTc is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the faster the heart rate the shorter the QTc. If a QTc >=500 milliseconds (msec) was noted on a scheduled or unscheduled electrocardiogram (ECG), then two additional ECGs should have been obtained within 5 minutes to confirm the abnormality. The average QTc was determined from the three ECG tracings by manual evaluation and was used to determine continued eligibility.

Outcome measures

Measure	Placebo n=69 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=70 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With the Indicated Worst-case On-therapy Shift From Baseline in Bazett's Corrected QT Interval (QTc) Any increase to >=450 msec	10 participants	5 participants
Number of Participants With the Indicated Worst-case On-therapy Shift From Baseline in Bazett's Corrected QT Interval (QTc) Increase to 481-500 msec	1 participants	1 participants
Number of Participants With the Indicated Worst-case On-therapy Shift From Baseline in Bazett's Corrected QT Interval (QTc) Increase to >=501 msec	2 participants	0 participants

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population. Data are presented for only those participants with laboratory values. The cut off for these data was October 12, 2012.

Grade shifts from Baseline were assessed as any grade increase (AGI), increase to Grade (G) 3 (ITG3), and increase to Grade 4 (ITG4). Toxicities were graded according to the National Cancer Institute common toxicity criteria (NCI-Common Toxicity Criteria for Adverse Events), version 4.0. Grade refers to the severity of the toxicity. The CTCAE displays Grades (G) 1 through 5 with unique clinical descriptions of severity for each toxicity based on the following general guideline: G1, mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; G2, moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); G3, severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; G4, Life-threatening consequences; urgent intervention indicated.; G5, death related to AE.

Outcome measures

Measure	Placebo n=69 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=71 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Hemoglobin, AGI	4 participants	14 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Hemoglobin, ITG3	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Hemoglobin, ITG4	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Lymphocytes, AGI	11 participants	9 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Lymphocytes, ITG3	2 participants	1 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Lymphocytes, ITG4	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Neutrophils, AGI	22 participants	55 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Neutrophils, ITG3	0 participants	11 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Neutrophils, ITG4	0 participants	2 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Platelets, AGI	10 participants	32 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Platelets, ITG3	0 participants	1 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade Platelets, ITG4	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade White blood cells, AGI	19 participants	48 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade White blood cells, ITG3	0 participants	2 participants
Number of Participants With the Indicated Worst-case On-therapy Hematology Parameter Grade Shifts From Baseline Grade White blood cells, ITG4	0 participants	0 participants

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population. Data are presented for only those participants with laboratory values. The cut off for these data was October 12, 2012.

Grade shifts from Baseline were assessed as any grade increase (AGI), increase to Grade (G) 3 (ITG3), and increase to Grade 4 (ITG4). Toxicities were graded according to the National Cancer Institute common toxicity criteria (NCI-Common Toxicity Criteria for Adverse Events), version 4.0. Grade refers to the severity of the toxicity. The CTCAE displays Grades (G) 1 through 5 with unique clinical descriptions of severity for each toxicity based on the following general guideline: G1, mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; G2, moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); G3, severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; G4, Life-threatening consequences; urgent intervention indicated.; G5, death related to AE.

Outcome measures

Measure	Placebo n=69 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=70 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Albumin, AGI, n=69, 70	2 participants	1 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Albumin, ITG3, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Albumin, ITG4, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Creatinine, AGI, n=69, 70	2 participants	2 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Creatinine, ITG3, n=69, 70	0 participants	1 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Creatinine, ITG4, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypercalcemia, AGI, n=69, 69	9 participants	3 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypercalcemia, ITG3, n=69, 69	1 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypercalcemia, ITG4, n=69, 69	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hyperglycemia, AGI, n=69, 70	16 participants	14 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hyperglycemia, ITG3, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hyperglycemia, ITG4, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hyperkalemia, AGI, n=69, 70	0 participants	1 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hyperkalemia, ITG3, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hyperkalemia, ITG4, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypermagnesemia, AGI, n=69, 69	6 participants	2 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypermagnesemia, ITG3, n=69, 69	1 participants	1 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypermagnesemia, ITG4, n=69, 69	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypernatremia, AGI, n=69, 70	2 participants	3 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypernatremia, ITG3, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypernatremia, ITG4, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypocalcemia, AGI, n=69, 69	4 participants	5 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypocalcemia, ITG3, n=69, 69	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypocalcemia, ITG4, n=69, 69	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypoglycemia, AGI, n=69, 70	0 participants	3 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypoglycemia, ITG3, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypoglycemia, ITG4, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypokalemia, AGI, n=69, 70	10 participants	6 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypokalemia, ITG3, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypokalemia, ITG4, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypomagnesemia, AGI, n=69, 69	6 participants	2 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypomagnesemia, ITG3, n=69, 69	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hypomagnesemia, ITG4, n=69, 69	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hyponatremia, AGI, n=69, 70	1 participants	1 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hyponatremia, ITG3, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Hyponatremia, ITG4, n=69, 70	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Phosphate, AGI, n=69, 69	2 participants	4 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Phosphate, ITG3, n=69, 69	0 participants	0 participants
Number of Participants With the Indicated Worst-case On-therapy Chemistry Parameter Grade Shifts From Baseline Grade Phosphate, ITG4, n=69, 69	0 participants	0 participants

SECONDARY outcome

Timeframe: From Week 1 until the end of the treatment period (up to Study Week 108)

Population: All Treated Population. The cut off for these data was October 12, 2012.

The ECOG performance status scales and criteria are used by doctors and researchers to assess how a participant's disease is progressing, assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. Grade 0, fully active, able to carry on all pre-disease performance without restriction. Grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Grade 2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50% of waking hours. Grade 3, capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. Grade 4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. Grade 5, dead.

Outcome measures

Measure	Placebo n=72 Participants Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=72 Participants Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Number of Participants With the Indicated Worst-case Eastern Cooperative Oncology Group (ECOG) Performance Status Shifts From Baseline Grades of 0, 1, and 2 Baseline score of 0; shift to 0	56 participants	46 participants
Number of Participants With the Indicated Worst-case Eastern Cooperative Oncology Group (ECOG) Performance Status Shifts From Baseline Grades of 0, 1, and 2 Baseline score of 0; shift to 1	2 participants	13 participants
Number of Participants With the Indicated Worst-case Eastern Cooperative Oncology Group (ECOG) Performance Status Shifts From Baseline Grades of 0, 1, and 2 Baseline score of 0; shift to 2	0 participants	0 participants
Number of Participants With the Indicated Worst-case Eastern Cooperative Oncology Group (ECOG) Performance Status Shifts From Baseline Grades of 0, 1, and 2 Baseline score of 1; shift to 0	0 participants	0 participants
Number of Participants With the Indicated Worst-case Eastern Cooperative Oncology Group (ECOG) Performance Status Shifts From Baseline Grades of 0, 1, and 2 Baseline score of 1; shift to 1	12 participants	13 participants
Number of Participants With the Indicated Worst-case Eastern Cooperative Oncology Group (ECOG) Performance Status Shifts From Baseline Grades of 0, 1, and 2 Baseline score of 1; shift to 2	1 participants	0 participants
Number of Participants With the Indicated Worst-case Eastern Cooperative Oncology Group (ECOG) Performance Status Shifts From Baseline Grades of 0, 1, and 2 Baseline score of 2; shift to 0	0 participants	0 participants
Number of Participants With the Indicated Worst-case Eastern Cooperative Oncology Group (ECOG) Performance Status Shifts From Baseline Grades of 0, 1, and 2 Baseline score of 2; shift to 1	0 participants	0 participants
Number of Participants With the Indicated Worst-case Eastern Cooperative Oncology Group (ECOG) Performance Status Shifts From Baseline Grades of 0, 1, and 2 Baseline score of 2; shift to 2	1 participants	0 participants

Adverse Events

Placebo

Serious events: 4 serious events

Other events: 59 other events

Deaths: 0 deaths

Pazopanib 800 Milligrams

Serious events: 7 serious events

Other events: 72 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=72 participants at risk Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=72 participants at risk Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Gastrointestinal disorders Ileus paralytic	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Gastrointestinal disorders Salivary gland calculus	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Hepatobiliary disorders Hepatic function abnormal	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Hepatobiliary disorders Liver injury	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
General disorders Thrombosis in device	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Investigations Alanine aminotransferase increased	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Investigations Aspartate aminotransferase increased	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Investigations Neutrophil count decreased	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Infections and infestations Urinary tract infection	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Nervous system disorders Cerebral artery stenosis	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Nervous system disorders Cerebral ischaemia	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Vascular disorders Hypertension	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Injury, poisoning and procedural complications Foot fracture	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.

Other adverse events

Measure	Placebo n=72 participants at risk Participants received matching placebo administered orally once daily for up to 24 months.	Pazopanib 800 Milligrams n=72 participants at risk Participants received pazopanib 800 milligrams administered orally once daily for up to 24 months.
Vascular disorders Hypertension	27.8% 20/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	76.4% 55/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Blood and lymphatic system disorders Neutropenia	22.2% 16/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	63.9% 46/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Blood and lymphatic system disorders Leukopenia	25.0% 18/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	54.2% 39/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Blood and lymphatic system disorders Thrombocytopenia	5.6% 4/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	23.6% 17/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Gastrointestinal disorders Diarrhoea	6.9% 5/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	48.6% 35/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Gastrointestinal disorders Abdominal pain	6.9% 5/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	15.3% 11/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Gastrointestinal disorders Nausea	4.2% 3/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	15.3% 11/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Gastrointestinal disorders Abdominal pain upper	2.8% 2/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	12.5% 9/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Gastrointestinal disorders Dyspepsia	6.9% 5/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	4.2% 3/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Gastrointestinal disorders Abdominal discomfort	5.6% 4/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	2.8% 2/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Gastrointestinal disorders Abdominal distension	5.6% 4/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	2.8% 2/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Skin and subcutaneous tissue disorders Hair colour changes	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	40.3% 29/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	2.8% 2/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	29.2% 21/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Skin and subcutaneous tissue disorders Rash	11.1% 8/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	5.6% 4/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Investigations Alanine aminotransferase increased	5.6% 4/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	26.4% 19/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Investigations Aspartate aminotransferase increased	8.3% 6/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	22.2% 16/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Investigations Blood thyroid stimulating hormone increased	2.8% 2/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	20.8% 15/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Investigations Blood lactate dehydrogenase increased	2.8% 2/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	9.7% 7/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Investigations Neutrophil count decreased	2.8% 2/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	8.3% 6/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Investigations Blood bilirubin increased	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	6.9% 5/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Investigations Protein urine present	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	8.3% 6/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Investigations Electrocardiogram QT prolonged	5.6% 4/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Nervous system disorders Headache	6.9% 5/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	18.1% 13/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Nervous system disorders Dizziness	4.2% 3/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	13.9% 10/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Infections and infestations Nasopharyngitis	12.5% 9/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	12.5% 9/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Infections and infestations Upper respiratory tract infection	6.9% 5/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	8.3% 6/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Infections and infestations Urinary tract infection	8.3% 6/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	6.9% 5/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
General disorders Fatigue	11.1% 8/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	19.4% 14/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
General disorders Chest discomfort	4.2% 3/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	5.6% 4/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
General disorders Pyrexia	5.6% 4/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	4.2% 3/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Musculoskeletal and connective tissue disorders Arthralgia	5.6% 4/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	9.7% 7/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Musculoskeletal and connective tissue disorders Pain in extremity	4.2% 3/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	5.6% 4/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Musculoskeletal and connective tissue disorders Back pain	2.8% 2/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	6.9% 5/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Musculoskeletal and connective tissue disorders Myalgia	6.9% 5/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	2.8% 2/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Metabolism and nutrition disorders Decreased appetite	1.4% 1/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	11.1% 8/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Renal and urinary disorders Proteinuria	0.00% 0/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	5.6% 4/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.
Psychiatric disorders Insomnia	6.9% 5/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.	2.8% 2/72 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Treated Population, comprised of all randomized participants who received at least one dose of investigational product. Treatment assignments in the All Treated Population were based on the actual treatment received, if different from the randomized treatment.

Additional Information

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