Trial Outcomes & Findings for Safety of Subcutaneous Methylnaltrexone for Opioid-Induced Constipation in Patients With Advanced Illness (NCT NCT00672139)

Last Updated: 2018-03-07

Results Overview

This was defined as the total number of days with a laxation (ie, a bowel movement) within 24 hours after dosing in each 7-day interval after the start of dosing. Results shown are the ranges (lowest and highest weekly values) of mean (± standard deviation) numbers of laxations within 24 hours of dosing per week during the 10-week treatment period for each group.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

156 participants

Primary outcome timeframe

10 weeks

Results posted on

2018-03-07

Participant Flow

Patients participated in this study at sites in Australia, Belgium, Brazil, Canada, France, Germany, Italy, Mexico, Spain, Sweden, the United Kingdom, and the United States.

The main eligibility criteria for this study were completion of 2 weeks of therapy and all post-baseline efficacy, safety, and health outcomes assessments in lead-in study MNTX4000 and an anticipated continued need for treatment of opioid-induced constipation.

Participant milestones

Participant milestones
Measure	Methylnaltrexone Bromide 8 mg Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.4 mL (8 mg) every other day if weight between 38 and \<62 kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.	Methylnaltrexone Bromide 12 mg Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.
Overall Study STARTED	57	92
Overall Study COMPLETED	27	47
Overall Study NOT COMPLETED	30	45

Reasons for withdrawal

Reasons for withdrawal
Measure	Methylnaltrexone Bromide 8 mg Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.4 mL (8 mg) every other day if weight between 38 and \<62 kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.	Methylnaltrexone Bromide 12 mg Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.
Overall Study Death	14	23
Overall Study Withdrawal by Subject	2	11
Overall Study Adverse Event	4	7
Overall Study Physician Decision	2	0
Overall Study Lack of Efficacy	4	1
Overall Study Protocol Violation	1	1
Overall Study hospice discharge, caregiver requests	3	2

Baseline Characteristics

Safety of Subcutaneous Methylnaltrexone for Opioid-Induced Constipation in Patients With Advanced Illness

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Methylnaltrexone Bromide 8 mg n=57 Participants Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.4 mL (8 mg) every other day if weight between 38 and \<62 kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.	Methylnaltrexone Bromide 12 mg n=92 Participants Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.	Total n=149 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	24 Participants n=5 Participants	46 Participants n=7 Participants	70 Participants n=5 Participants
Age, Categorical >=65 years	33 Participants n=5 Participants	46 Participants n=7 Participants	79 Participants n=5 Participants
Age, Continuous	68.07 years STANDARD_DEVIATION 14.29 • n=5 Participants	64.59 years STANDARD_DEVIATION 11.98 • n=7 Participants	65.92 years STANDARD_DEVIATION 12.98 • n=5 Participants
Sex: Female, Male Female	44 Participants n=5 Participants	33 Participants n=7 Participants	77 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	59 Participants n=7 Participants	72 Participants n=5 Participants
Underlying Advanced Illness Cancer	36 Participants n=5 Participants	49 Participants n=7 Participants	85 Participants n=5 Participants
Underlying Advanced Illness Pulmonary disease	7 Participants n=5 Participants	18 Participants n=7 Participants	25 Participants n=5 Participants
Underlying Advanced Illness Cardiovascular disease	4 Participants n=5 Participants	15 Participants n=7 Participants	19 Participants n=5 Participants
Underlying Advanced Illness Neurologic disease	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Underlying Advanced Illness Other	7 Participants n=5 Participants	7 Participants n=7 Participants	14 Participants n=5 Participants
Weight 38 to < 62 kg	54 participants n=5 Participants	0 participants n=7 Participants	54 participants n=5 Participants
Weight ≥ 62 kg	3 participants n=5 Participants	92 participants n=7 Participants	95 participants n=5 Participants
Glomerular filtration rate < 30 mL/min/1.73 m^2	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Glomerular filtration rate ≥ 30 mL/min/1.73 m^2	54 participants n=5 Participants	89 participants n=7 Participants	143 participants n=5 Participants
Glomerular filtration rate Missing	1 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants

PRIMARY outcome

Timeframe: 10 weeks

Population: The analysis population included subjects who received study drug and had laxation data and drug administration data. Two subjects in the 12 mg/day group had no drug administration data and were not included in efficacy analyses (but they were included in baseline characteristics and safety analyses).

Outcome measures

Outcome measures
Measure	Methylnaltrexone Bromide 8 mg n=57 Participants Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.4 mL (8 mg) every other day if weight between 38 and \<62 kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.	Methylnaltrexone Bromide 12 mg n=90 Participants Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.
Number of Laxations Per Subject Within 24 Hours of Dosing Per Week. Highest weekly average # laxations/week	2.6 Number of laxations Standard Deviation 2.4	3.4 Number of laxations Standard Deviation 3.4
Number of Laxations Per Subject Within 24 Hours of Dosing Per Week. Lowest weekly average # laxations/week	1.7 Number of laxations Standard Deviation 1.5	2.4 Number of laxations Standard Deviation 2.3

Adverse Events

Methylnaltrexone Bromide 8 mg

Serious events: 22 serious events

Other events: 45 other events

Deaths: 0 deaths

Methylnaltrexone Bromide 12 mg

Serious events: 37 serious events

Other events: 60 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 Bromide 8 mg n=57 participants at risk Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.4 mL (8 mg) every other day if weight between 38 and \<62 kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.	Methylnaltrexone Bromide 12 mg n=92 participants at risk Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.
Blood and lymphatic system disorders Anemia	5.3% 3/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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 Thrombocytopenia	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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.
Cardiac disorders Arrhythmia	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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.
Cardiac disorders Cardiac failure congestive	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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.
Cardiac disorders Myocardial infarction	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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 Constipation	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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.	3.3% 3/92 • Adverse events were collected over the 10-week treatment 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% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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 Dysphagia	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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 Intestinal obstruction	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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	26.3% 15/57 • Adverse events were collected over the 10-week treatment 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.	23.9% 22/92 • Adverse events were collected over the 10-week treatment 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 General physical health deterioration	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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 Campylobacter infection	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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 Cellulitis	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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 Pneumonia	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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 Sepsis	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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 Septic shock	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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 Urosepsis	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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.
Injury, poisoning and procedural complications Fall	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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.
Injury, poisoning and procedural complications Femoral neck fracture	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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.
Injury, poisoning and procedural complications Hip fracture	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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.
Injury, poisoning and procedural complications Wound	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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 Dehydration	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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 Hypoglycemia	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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 Pathological fracture	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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 Cerebrovascular accident	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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 Confusional state	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	2.2% 2/92 • Adverse events were collected over the 10-week treatment 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 Suicidal ideation	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	2.2% 2/92 • Adverse events were collected over the 10-week treatment 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 Hematuria	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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 Renal failure	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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 Urinary retention	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	2.2% 2/92 • Adverse events were collected over the 10-week treatment 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 Pleuritic pain	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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 Bromide 8 mg n=57 participants at risk Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.4 mL (8 mg) every other day if weight between 38 and \<62 kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.	Methylnaltrexone Bromide 12 mg n=92 participants at risk Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.
Gastrointestinal disorders Abdominal pain	22.8% 13/57 • Adverse events were collected over the 10-week treatment 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.	22.8% 21/92 • Adverse events were collected over the 10-week treatment 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	19.3% 11/57 • Adverse events were collected over the 10-week treatment 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.	13.0% 12/92 • Adverse events were collected over the 10-week treatment 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 Dysphagia	5.3% 3/57 • Adverse events were collected over the 10-week treatment 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.	3.3% 3/92 • Adverse events were collected over the 10-week treatment 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 Flatulence	5.3% 3/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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	8.8% 5/57 • Adverse events were collected over the 10-week treatment 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.	15.2% 14/92 • Adverse events were collected over the 10-week treatment 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	7.0% 4/57 • Adverse events were collected over the 10-week treatment 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.	5.4% 5/92 • Adverse events were collected over the 10-week treatment 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	17.5% 10/57 • Adverse events were collected over the 10-week treatment 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.	8.7% 8/92 • Adverse events were collected over the 10-week treatment 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 pain	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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.	5.4% 5/92 • Adverse events were collected over the 10-week treatment 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	7.0% 4/57 • Adverse events were collected over the 10-week treatment 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.	4.3% 4/92 • Adverse events were collected over the 10-week treatment 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	5.3% 3/57 • Adverse events were collected over the 10-week treatment 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.	3.3% 3/92 • Adverse events were collected over the 10-week treatment 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 Oedema peripheral	17.5% 10/57 • Adverse events were collected over the 10-week treatment 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.	14.1% 13/92 • Adverse events were collected over the 10-week treatment 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	1.8% 1/57 • Adverse events were collected over the 10-week treatment 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.	10.9% 10/92 • Adverse events were collected over the 10-week treatment 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	10.5% 6/57 • Adverse events were collected over the 10-week treatment 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.	7.6% 7/92 • Adverse events were collected over the 10-week treatment 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.
Injury, poisoning and procedural complications Contusion	12.3% 7/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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.
Injury, poisoning and procedural complications Fall	14.0% 8/57 • Adverse events were collected over the 10-week treatment 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.	13.0% 12/92 • Adverse events were collected over the 10-week treatment 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.
Injury, poisoning and procedural complications Laceration	5.3% 3/57 • Adverse events were collected over the 10-week treatment 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.	2.2% 2/92 • Adverse events were collected over the 10-week treatment 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	7.0% 4/57 • Adverse events were collected over the 10-week treatment 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.	5.4% 5/92 • Adverse events were collected over the 10-week treatment 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 Dehydration	7.0% 4/57 • Adverse events were collected over the 10-week treatment 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.	2.2% 2/92 • Adverse events were collected over the 10-week treatment 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	5.3% 3/57 • Adverse events were collected over the 10-week treatment 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.	1.1% 1/92 • Adverse events were collected over the 10-week treatment 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% 0/57 • Adverse events were collected over the 10-week treatment 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.	5.4% 5/92 • Adverse events were collected over the 10-week treatment 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	7.0% 4/57 • Adverse events were collected over the 10-week treatment 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% 6/92 • Adverse events were collected over the 10-week treatment 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 Lethargy	7.0% 4/57 • Adverse events were collected over the 10-week treatment 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.	3.3% 3/92 • Adverse events were collected over the 10-week treatment 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 Agitation	8.8% 5/57 • Adverse events were collected over the 10-week treatment 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.	7.6% 7/92 • Adverse events were collected over the 10-week treatment 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 Anxiety	7.0% 4/57 • Adverse events were collected over the 10-week treatment 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.	7.6% 7/92 • Adverse events were collected over the 10-week treatment 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 Confusional state	15.8% 9/57 • Adverse events were collected over the 10-week treatment 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.	12.0% 11/92 • Adverse events were collected over the 10-week treatment 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 Restlessness	5.3% 3/57 • Adverse events were collected over the 10-week treatment 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.	3.3% 3/92 • Adverse events were collected over the 10-week treatment 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	5.3% 3/57 • Adverse events were collected over the 10-week treatment 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.	5.4% 5/92 • Adverse events were collected over the 10-week treatment 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 Dyspnoea	12.3% 7/57 • Adverse events were collected over the 10-week treatment 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.	9.8% 9/92 • Adverse events were collected over the 10-week treatment 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 Rales	7.0% 4/57 • Adverse events were collected over the 10-week treatment 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% 0/92 • Adverse events were collected over the 10-week treatment 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	0.00% 0/57 • Adverse events were collected over the 10-week treatment 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.	5.4% 5/92 • Adverse events were collected over the 10-week treatment 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.