Trial Outcomes & Findings for Efficacy and Safety of Naldemedine in Treating Opioid-induced Constipation (NCT NCT01993940)

NCT ID: NCT01993940

Last Updated: 2017-05-30

Results Overview

A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of rescue laxative therapy during the 24 hours prior to the BM. A responder was defined as a participant having 9 or more positive response weeks out of the 12-week Treatment Period and 3 positive response weeks out of last 4 weeks of the 12-week Treatment Period. A positive response week was defined as ≥ 3 SBMs per week and an increase from baseline of ≥ 1 SBM per week for that week. If a participant had less than 4 days of diary entries for a week, that week was treated as a "non-response" week. Any participant with insufficient primary endpoint data (data for less than 9 out of the 12 weeks of the Treatment Period or less than 3 out of the last 4 weeks of the 12-week Treatment Period) was treated as a non-responder

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 553 participants
• Primary outcome timeframe: 12-week treatment period
• Results posted on: 2017-05-30

Participant Flow

Participants were randomized at 69 sites in North America and Europe, including Austria, Czech Republic, Germany, Poland, Spain, and the United States.

Participants were randomized in a 1:1 ratio to 0.2 mg naldemedine or placebo for 12 weeks. Randomization was stratified based on documented opioid use (average total daily dose (TDD) during the 14-consecutive-day qualifying period) as follows: * 30 to 100 mg equivalents of oral morphine sulfate * > 100 mg equivalents of oral morphine sulfate

Participant milestones

Measure	Naldemedine Participants received 0.2 mg naldemedine orally once daily for 12 weeks.	Placebo Participants received placebo orally once daily for 12 weeks.
Overall Study STARTED	277	276
Overall Study Received Treatment	272	276
Overall Study COMPLETED	237	232
Overall Study NOT COMPLETED	40	44

Reasons for withdrawal

Measure	Naldemedine Participants received 0.2 mg naldemedine orally once daily for 12 weeks.	Placebo Participants received placebo orally once daily for 12 weeks.
Overall Study Adverse Event	16	11
Overall Study Withdrawal by Subject	15	19
Overall Study Lost to Follow-up	2	5
Overall Study Protocol Violation	5	8
Overall Study Death	1	0
Overall Study Other - Miscellaneous	1	1

Baseline Characteristics

Efficacy and Safety of Naldemedine in Treating Opioid-induced Constipation

Baseline characteristics by cohort

Measure	Naldemedine n=276 Participants Participants received 0.2 mg naldemedine orally once daily for 12 weeks.	Placebo n=274 Participants Participants received placebo orally once daily for 12 weeks.	Total n=550 Participants Total of all reporting groups
Age, Continuous	54.1 Years STANDARD_DEVIATION 10.48 • n=5 Participants	52.9 Years STANDARD_DEVIATION 11.40 • n=7 Participants	53.5 Years STANDARD_DEVIATION 10.96 • n=5 Participants
Age, Customized < 40 years	22 participants n=5 Participants	40 participants n=7 Participants	62 participants n=5 Participants
Age, Customized ≥ 40 to < 65 years	210 participants n=5 Participants	196 participants n=7 Participants	406 participants n=5 Participants
Age, Customized ≥ 65 years	44 participants n=5 Participants	38 participants n=7 Participants	82 participants n=5 Participants
Sex: Female, Male Female	165 Participants n=5 Participants	168 Participants n=7 Participants	333 Participants n=5 Participants
Sex: Female, Male Male	111 Participants n=5 Participants	106 Participants n=7 Participants	217 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	26 Participants n=5 Participants	27 Participants n=7 Participants	53 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	250 Participants n=5 Participants	247 Participants n=7 Participants	497 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	3 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants
Race/Ethnicity, Customized Asian	2 participants n=5 Participants	3 participants n=7 Participants	5 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	49 participants n=5 Participants	39 participants n=7 Participants	88 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized White	222 participants n=5 Participants	227 participants n=7 Participants	449 participants n=5 Participants
Stratification by Opioid Dose 30-100 mg	169 participants n=5 Participants	167 participants n=7 Participants	336 participants n=5 Participants
Stratification by Opioid Dose > 100 mg	107 participants n=5 Participants	107 participants n=7 Participants	214 participants n=5 Participants
Spontaneous Bowel Movements per Week	1.16 spontaneous bowel movements / week STANDARD_DEVIATION 0.755 • n=5 Participants	1.17 spontaneous bowel movements / week STANDARD_DEVIATION 0.730 • n=7 Participants	1.17 spontaneous bowel movements / week STANDARD_DEVIATION 0.742 • n=5 Participants

PRIMARY outcome

Timeframe: 12-week treatment period

Population: Intent-to-treat population

A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of rescue laxative therapy during the 24 hours prior to the BM.

A responder was defined as a participant having 9 or more positive response weeks out of the 12-week Treatment Period and 3 positive response weeks out of last 4 weeks of the 12-week Treatment Period. A positive response week was defined as ≥ 3 SBMs per week and an increase from baseline of ≥ 1 SBM per week for that week. If a participant had less than 4 days of diary entries for a week, that week was treated as a "non-response" week.

Any participant with insufficient primary endpoint data (data for less than 9 out of the 12 weeks of the Treatment Period or less than 3 out of the last 4 weeks of the 12-week Treatment Period) was treated as a non-responder

Outcome measures

Measure	Naldemedine n=276 Participants Participants received 0.2 mg naldemedine orally once daily for 12 weeks.	Placebo n=274 Participants Participants received placebo orally once daily for 12 weeks.
Percentage of Participants With a Spontaneous Bowel Movement (SBM) Response	52.5 percentage of participants Interval 46.5 to 58.6	33.6 percentage of participants Interval 28.0 to 39.5

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)

Population: Intent-to-treat population

A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of a rescue laxative therapy during the 24 hours prior to the BM. Baseline was defined as the 14 days in the screening period prior to study drug administration.

Outcome measures

Measure	Naldemedine n=276 Participants Participants received 0.2 mg naldemedine orally once daily for 12 weeks.	Placebo n=274 Participants Participants received placebo orally once daily for 12 weeks.
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week	3.56 spontaneous bowel movements / week Standard Error 0.174	2.16 spontaneous bowel movements / week Standard Error 0.174

SECONDARY outcome

Timeframe: Baseline and Week 1

Population: Intent-to-treat population

A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of a rescue laxative therapy during the 24 hours prior to the BM. Baseline was defined as the 14 days in the screening period prior to study drug administration.

Outcome measures

Measure	Naldemedine n=276 Participants Participants received 0.2 mg naldemedine orally once daily for 12 weeks.	Placebo n=274 Participants Participants received placebo orally once daily for 12 weeks.
Change From Baseline to Week 1 in the Number of Spontaneous Bowel Movements Per Week	3.86 spontaneous bowel movements / week Standard Error 0.199	1.69 spontaneous bowel movements / week Standard Error 0.198

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)

Population: Intent-to-treat population

A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. A complete spontaneous bowel movement (CSBM) was defined as an SBM which was accompanied by the feeling of complete evacuation.

Outcome measures

Measure	Naldemedine n=276 Participants Participants received 0.2 mg naldemedine orally once daily for 12 weeks.	Placebo n=274 Participants Participants received placebo orally once daily for 12 weeks.
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements Per Week	2.77 complete spontaneous BMs / week Standard Error 0.166	1.62 complete spontaneous BMs / week Standard Error 0.166

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)

Population: Intent-to-treat population

A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. The severity of straining with each bowel movement was assessed on the following scale: 0=no straining, 1=mild straining, 2=moderate straining, 3=severe straining, 4=very severe straining. SBMs without straining were defined as SBMs with a straining score of 0.

Outcome measures

Measure	Naldemedine n=276 Participants Participants received 0.2 mg naldemedine orally once daily for 12 weeks.	Placebo n=274 Participants Participants received placebo orally once daily for 12 weeks.
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements With No Straining Per Week	1.85 SBMs with no straining / week Standard Error 0.163	1.10 SBMs with no straining / week Standard Error 0.162

Adverse Events

Naldemedine

Serious events: 9 serious events

Other events: 37 other events

Deaths: 0 deaths

Placebo

Serious events: 13 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Measure	Naldemedine n=271 participants at risk Participants received 0.2 mg naldemedine orally once daily for 12 weeks.	Placebo n=274 participants at risk Participants received placebo orally once daily for 12 weeks.
Infections and infestations Gastroenteritis Viral	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Infections and infestations Herpes Zoster	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Infections and infestations Pneumonia	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Infections and infestations Pneumonia Influenzal	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Infections and infestations Sepsis	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Infections and infestations Urinary Tract Infection	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder Transitional Cell Carcinoma	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Blood and lymphatic system disorders Lymphadenopathy Mediastinal	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Metabolism and nutrition disorders Dehydration	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Metabolism and nutrition disorders Hypomagnesaemia	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Psychiatric disorders Mental Status Changes	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Psychiatric disorders Psychotic Disorder	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Nervous system disorders Convulsion	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Nervous system disorders Sciatica	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Nervous system disorders Syncope	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.73% 2/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Cardiac disorders Cardiac Failure Congestive	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Cardiac disorders Sick Sinus Syndrome	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Vascular disorders Hypotension	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Respiratory, thoracic and mediastinal disorders Chronic Obstructive Pulmonary Disease	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Gastrointestinal disorders Colitis Ischaemic	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Gastrointestinal disorders Duodenitis	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Gastrointestinal disorders Enterocolitis	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Gastrointestinal disorders Gastritis	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Gastrointestinal disorders Vomiting	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Hepatobiliary disorders Cholelithiasis	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Musculoskeletal and connective tissue disorders Musculoskeletal Chest Pain	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.73% 2/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Renal and urinary disorders Renal Failure Acute	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Injury, poisoning and procedural complications Overdose	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Injury, poisoning and procedural complications Radius Fracture	0.37% 1/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.00% 0/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Injury, poisoning and procedural complications Tendon Rupture	0.00% 0/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	0.36% 1/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.

Other adverse events

Measure	Naldemedine n=271 participants at risk Participants received 0.2 mg naldemedine orally once daily for 12 weeks.	Placebo n=274 participants at risk Participants received placebo orally once daily for 12 weeks.
Infections and infestations Urinary Tract Infection	1.8% 5/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	5.1% 14/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Gastrointestinal disorders Abdominal Pain	5.2% 14/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	1.1% 3/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.
Gastrointestinal disorders Diarrhoea	8.9% 24/271 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.	1.8% 5/274 • From the first dose up to 28 days after the last dose of study drug (16 weeks). The Safety Population included all randomized participants who received at least 1 dose of study drug and were analyzed by the treatment actually received. Three participants (one in the naldemedine arm and two in the placebo arm) were excluded due to double enrollment at different sites.

Additional Information

Shionogi Clinical Trials Administrator

Shionogi Inc.

Phone: 800-849-9707

Email: shionogiclintrials-admin@shionogi.co.jp

Results disclosure agreements

• Principal investigator is a sponsor employee The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.
• Publication restrictions are in place

Restriction type: OTHER