Trial Outcomes & Findings for Study Evaluating the Efficacy and Safety of Subcutaneous Methylnaltrexone (MOA-728) for the Treatment of Opioid-Induced-Constipation (NCT NCT00936884)

Last Updated: 2020-01-02

Results Overview

There were 2 co-primary endpoints for this study. This measurement is the first of the 2 co-primary endpoints. This endpoint measures the percentage of patients who had an RFBM within 4 hours after the first dose of test article during the double-blind period; data are expressed as percentages of patients for the MNTX and placebo groups. To qualify as rescue free, the bowel movement could not occur within 6 hours after a rectal intervention (ie, rectal suppository, enema, manual disimpaction). Note that efficacy results (primary and secondary outcomes) are presented for the double-blind period only. Therefore, no efficacy results are presented for the open-label period.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

50 participants

Primary outcome timeframe

Up to 4 hours after the first injection

Results posted on

2020-01-02

Participant Flow

Participant milestones

Participant milestones
Measure	Methylnaltrexone Double-blind Methylnaltrexone once every other day.	Placebo Placebo once every other day.	Methylnaltrexone Open-label Subjects who completed the double-blind period had the option to receive methylnaltrexone once every other day during a 12-week, open-label extension period.
Double-blind STARTED	25	25	0
Double-blind COMPLETED	13	18	0
Double-blind NOT COMPLETED	12	7	0
Open-label STARTED	0	0	31
Open-label COMPLETED	0	0	12
Open-label NOT COMPLETED	0	0	19

Reasons for withdrawal

Reasons for withdrawal
Measure	Methylnaltrexone Double-blind Methylnaltrexone once every other day.	Placebo Placebo once every other day.
Double-blind Withdrawal by Subject	6	4
Double-blind Death	2	1
Double-blind Lack of Efficacy	1	1
Double-blind Adverse Event	1	0
Double-blind Physician Decision	1	0
Double-blind No post baseline diary entry	1	0
Double-blind Did not receive study drug	0	1

Baseline Characteristics

Study Evaluating the Efficacy and Safety of Subcutaneous Methylnaltrexone (MOA-728) for the Treatment of Opioid-Induced-Constipation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Methylnaltrexone Double-blind n=25 Participants Methylnaltrexone once every other day. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg; 0.4 mL (8 mg) every other day if weight between 38 and \< 62 kg; or 0.0075 mL/kg (0.15 mg/kg) every other day if weight between 27 and \<38 kg.	Placebo n=25 Participants Placebo once every other day. Subjects received matching placebo injections.	Total n=50 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	18 Participants n=5 Participants	13 Participants n=7 Participants	31 Participants n=5 Participants
Age, Categorical >=65 years	7 Participants n=5 Participants	12 Participants n=7 Participants	19 Participants n=5 Participants
Age, Continuous	58.5 years STANDARD_DEVIATION 11.68 • n=5 Participants	62.1 years STANDARD_DEVIATION 14.23 • n=7 Participants	60.3 years STANDARD_DEVIATION 13.01 • n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants	11 Participants n=7 Participants	25 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	14 Participants n=7 Participants	25 Participants n=5 Participants
Eastern Cooperative Oncology Group Score 0 - Fully active	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Eastern Cooperative Oncology Group Score 1 - Restricted in strenuous activity	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Eastern Cooperative Oncology Group Score 2 - Unable to work	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Eastern Cooperative Oncology Group Score 3 - Limited self-care	16 Participants n=5 Participants	15 Participants n=7 Participants	31 Participants n=5 Participants
Hospitalization Status at Screening Period Yes	12 participants n=5 Participants	8 participants n=7 Participants	20 participants n=5 Participants
Hospitalization Status at Screening Period No	13 participants n=5 Participants	17 participants n=7 Participants	30 participants n=5 Participants
Underlying Advanced Illness - Cancer-related illness	25 Participants n=5 Participants	25 Participants n=7 Participants	50 Participants n=5 Participants
Weight < 38 kg	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Weight 38 - < 62 kg	17 Participants n=5 Participants	20 Participants n=7 Participants	37 Participants n=5 Participants
Weight ≥62 kg	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants
Weight Missing	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 4 hours after the first injection

Population: Although 25 patients in the MNTX group and 24 in the placebo group received study drug, 24 and 23 patients, respectively, had ≥ 1 post baseline diary assessment and were analyzed for efficacy.

Outcome measures

Outcome measures
Measure	Methylnaltrexone Double-blind n=24 Participants Methylnaltrexone once every other day. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg; 0.4 mL (8 mg) every other day if weight between 38 and \< 62 kg; or 0.0075 mL/kg (0.15 mg/kg) every other day if weight between 27 and \<38 kg.	Placebo n=23 Participants Placebo once every other day. Subjects received matching placebo injections.
The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After the First Injection.	79.2 percentage of participants	4.3 percentage of participants

PRIMARY outcome

Timeframe: Within 4 Hours After Each Dose During the 2 weeks Double-Blind Period

This measurement is the second of the 2 co-primary endpoints. This endpoint measures the percentage of patients who had an RFBM within 4 hours after each dose of test article during the double-blind period; data are expressed as percentages of patients by dose (first, second, third, fourth, etc.) for the MNTX and placebo groups. The definition of RFBM is described above (see first co-primary endpoint).

Outcome measures

Outcome measures
Measure	Methylnaltrexone Double-blind n=24 Participants Methylnaltrexone once every other day. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg; 0.4 mL (8 mg) every other day if weight between 38 and \< 62 kg; or 0.0075 mL/kg (0.15 mg/kg) every other day if weight between 27 and \<38 kg.	Placebo n=23 Participants Placebo once every other day. Subjects received matching placebo injections.
The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. RFBM post second DB injection	61.9 percentage of participants	8.7 percentage of participants
The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. RFBM post third DB injection	52.6 percentage of participants	8.7 percentage of participants
The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. RFBM post fourth DB injection	38.9 percentage of participants	8.7 percentage of participants
The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. RFBM post fifth DB injection	56.3 percentage of participants	4.5 percentage of participants
The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. RFBM post sixth DB injection	43.8 percentage of participants	0 percentage of participants
The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. RFBM post seventh DB injection	43.8 percentage of participants	0 percentage of participants
The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. RFBM post eighth DB injection	57.1 percentage of participants	7.7 percentage of participants

SECONDARY outcome

Timeframe: Within 4 Hours After Each Dose During the 2 weeks Double-Blind Period

This endpoint measures the percentage of injections resulting in RFBMs within 4 hours after test article administration during the double-blind period. The percentage of injections resulting in RFBMs is calculated for each patient and then data are expressed as the mean (± standard deviation) percentage for the MNTX and placebo groups. The definition of RFBM is described above (see first co-primary endpoint).

Outcome measures

Outcome measures
Measure	Methylnaltrexone Double-blind n=24 Participants Methylnaltrexone once every other day. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg; 0.4 mL (8 mg) every other day if weight between 38 and \< 62 kg; or 0.0075 mL/kg (0.15 mg/kg) every other day if weight between 27 and \<38 kg.	Placebo n=23 Participants Placebo once every other day. Subjects received matching placebo injections.
Percentage of Injections Resulting in RFBM Within 4 Hours After Test Article Administration.	61.61 percentage of injections Standard Deviation 36.520	4.97 percentage of injections Standard Deviation 22.203

Adverse Events

Methylnaltrexone Double-blind

Serious events: 12 serious events

Other events: 16 other events

Deaths: 0 deaths

Placebo

Serious events: 8 serious events

Other events: 18 other events

Deaths: 0 deaths

Methylnaltrexone Open-label

Serious events: 21 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

David Sorscher

Salix Pharmaceuticals

Phone: 919-862-1827

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	Methylnaltrexone Double-blind n=25 participants at risk Methylnaltrexone once every other day. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg; 0.4 mL (8 mg) every other day if weight between 38 and \< 62 kg; or 0.0075 mL/kg (0.15 mg/kg) every other day if weight between 27 and \<38 kg.	Placebo n=24 participants at risk Placebo once every other day. Subjects received matching placebo injections.	Methylnaltrexone Open-label n=31 participants at risk Subjects who completed the double-blind period had the option to receive methylnaltrexone once every other day during a 12-week, open-label extension period.
Gastrointestinal disorders Abdominal distension	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Abdominal pain	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Nausea	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Vomiting	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Asthenia	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	8.3% 2/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	29.0% 9/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Disease progression	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	12.9% 4/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	16.0% 4/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	20.8% 5/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	29.0% 9/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Nervous system disorders Somnolence	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Renal and urinary disorders Dysuria	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Respiratory, thoracic and mediastinal disorders Dyspnea	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	8.3% 2/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Malignant neoplasm progression	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Blood and lymphatic system disorders Leukopenia	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Chest discomfort	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Infections and infestations Herpes zoster	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Musculoskeletal and connective tissue disorders Muscular weakness	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Mesothelioma malignant advanced	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Nervous system disorders Diplegia	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Nervous system disorders Hepatic encephalopathy	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Nervous system disorders Syncope	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Abdominal discomfort	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Ascites	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Diarrhea	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Gingival bleeding	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Melena	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Feeling cold	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Non-cardiac chest pain	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Pain	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Pyrexia	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Hepatobiliary disorders Hepatic failure	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic gastric cancer	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Nervous system disorders Headache	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Respiratory, thoracic and mediastinal disorders Hemoptysis	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Respiratory, thoracic and mediastinal disorders Sputum increased	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.

Other adverse events
Measure	Methylnaltrexone Double-blind n=25 participants at risk Methylnaltrexone once every other day. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg; 0.4 mL (8 mg) every other day if weight between 38 and \< 62 kg; or 0.0075 mL/kg (0.15 mg/kg) every other day if weight between 27 and \<38 kg.	Placebo n=24 participants at risk Placebo once every other day. Subjects received matching placebo injections.	Methylnaltrexone Open-label n=31 participants at risk Subjects who completed the double-blind period had the option to receive methylnaltrexone once every other day during a 12-week, open-label extension period.
Blood and lymphatic system disorders Anemia	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	12.5% 3/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	12.9% 4/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Abdominal distension	8.0% 2/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	8.3% 2/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	9.7% 3/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Abdominal pain	16.0% 4/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Ascites	16.0% 4/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	12.5% 3/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Diarrhoea	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	8.3% 2/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	12.9% 4/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Nausea	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	8.3% 2/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Gastrointestinal disorders Vomiting	8.0% 2/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	9.7% 3/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Asthenia	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	29.0% 9/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Edema	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	9.7% 3/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Edema peripheral	12.0% 3/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	9.7% 3/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Fatigue	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	8.3% 2/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Pain	8.0% 2/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
General disorders Pyrexia	12.0% 3/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Hepatobiliary disorders Jaundice	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	8.3% 2/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Infections and infestations Urinary tract infection	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Metabolism and nutrition disorders Decreased appetite	8.0% 2/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	22.6% 7/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Metabolism and nutrition disorders Hypoalbuminemia	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	9.7% 3/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Musculoskeletal and connective tissue disorders Back pain	8.0% 2/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Musculoskeletal and connective tissue disorders Pain in extremity	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	9.7% 3/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Nervous system disorders Dizziness	12.0% 3/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Nervous system disorders Headache	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Nervous system disorders Somnolence	8.0% 2/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Renal and urinary disorders Dysuria	16.0% 4/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	12.5% 3/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Psychiatric disorders Delirium	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Psychiatric disorders Insomnia	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	8.3% 2/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	9.7% 3/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Respiratory, thoracic and mediastinal disorders Dyspnea	8.0% 2/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	4.2% 1/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	9.7% 3/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Respiratory, thoracic and mediastinal disorders Productive cough	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	6.5% 2/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Skin and subcutaneous tissue disorders Hyperhidrosis	8.0% 2/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	0.00% 0/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Vascular disorders Hypotension	4.0% 1/25 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	8.3% 2/24 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.	3.2% 1/31 • Adverse events were collected over the 2-week double-blind period and over the 12-week open-label period. Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.