Trial Outcomes & Findings for Long Term Safety of Naldemedine (NCT NCT01965652)

NCT ID: NCT01965652

Last Updated: 2018-04-18

Results Overview

A serious adverse event was defined as any adverse event (AE) that resulted in any of the following outcomes: death, life-threatening AE, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life threatening, or require hospitalization were considered an SAE when, based upon appropriate medical judgment, they jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above. Adverse drug reactions (ADRs) were defined as adverse events that were considered by the investigator to be definitely, probably, or possibly related to study drug. Serious ADRs were defined as serious AEs considered by the investigator to be definitely, probably, or possibly related to study drug.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1246 participants

Primary outcome timeframe

From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks).

Results posted on

2018-04-18

Participant Flow

This study was conducted at 195 clinical sites in North America (Canada and the United States), Europe (Belgium, Denmark, Estonia, France, Germany, Hungary, Poland, Spain, Sweden, and the United Kingdom), and Africa/Asia Pacific (Australia and South Africa)

Participants were randomized in a 1:1 ratio to receive naldemedine or placebo for 52 weeks. Randomization was stratified based on documented opioid use (average total daily dose \[TDD\] during the 14-consecutive-day qualifying period) as follows: * 30 - 100 mg equivalents of oral morphine sulfate. * \> 100 mg equivalents of oral morphine sulfate.

Participant milestones

Participant milestones
Measure	Naldemedine Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo Participants received placebo tablets orally once daily for 52 weeks.
Overall Study STARTED	623	623
Overall Study Received Treatment	622	623
Overall Study COMPLETED	413	413
Overall Study NOT COMPLETED	210	210

Reasons for withdrawal

Reasons for withdrawal
Measure	Naldemedine Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo Participants received placebo tablets orally once daily for 52 weeks.
Overall Study Adverse Event	40	37
Overall Study Withdrawal by Subject	62	69
Overall Study Lost to Follow-up	53	40
Overall Study Protocol Violation	34	38
Overall Study Death	3	4
Overall Study Other - Miscellaneous	18	21
Overall Study Pregnancy	0	1

Baseline Characteristics

Long Term Safety of Naldemedine

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=619 Participants Participants received placebo tablets orally once daily for 52 weeks.	Total n=1240 Participants Total of all reporting groups
Age, Continuous	53.4 Years STANDARD_DEVIATION 11.68 • n=5 Participants	52.7 Years STANDARD_DEVIATION 10.55 • n=7 Participants	53.0 Years STANDARD_DEVIATION 11.13 • n=5 Participants
Age, Customized < 40 years	75 participants n=5 Participants	68 participants n=7 Participants	143 participants n=5 Participants
Age, Customized ≥ 40 to < 65 years	445 participants n=5 Participants	475 participants n=7 Participants	920 participants n=5 Participants
Age, Customized ≥ 65 years	101 participants n=5 Participants	76 participants n=7 Participants	177 participants n=5 Participants
Sex: Female, Male Female	383 Participants n=5 Participants	402 Participants n=7 Participants	785 Participants n=5 Participants
Sex: Female, Male Male	238 Participants n=5 Participants	217 Participants n=7 Participants	455 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	47 Participants n=5 Participants	42 Participants n=7 Participants	89 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	574 Participants n=5 Participants	577 Participants n=7 Participants	1151 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	2 participants n=5 Participants	7 participants n=7 Participants	9 participants n=5 Participants
Race/Ethnicity, Customized Asian	5 participants n=5 Participants	7 participants n=7 Participants	12 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	120 participants n=5 Participants	108 participants n=7 Participants	228 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	2 participants n=5 Participants	1 participants n=7 Participants	3 participants n=5 Participants
Race/Ethnicity, Customized White	492 participants n=5 Participants	496 participants n=7 Participants	988 participants n=5 Participants
Stratification by Opioid Dose 30-100 mg	396 participants n=5 Participants	392 participants n=7 Participants	788 participants n=5 Participants
Stratification by Opioid Dose > 100 mg	225 participants n=5 Participants	227 participants n=7 Participants	452 participants n=5 Participants

PRIMARY outcome

Timeframe: From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks).

Population: Safety population

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=619 Participants Participants received placebo tablets orally once daily for 52 weeks.
Number of Participants With Adverse Events Adverse events	425 participants	446 participants
Number of Participants With Adverse Events Adverse drug reactions	149 participants	121 participants
Number of Participants With Adverse Events AEs leading to discontinuation of study drug	39 participants	36 participants
Number of Participants With Adverse Events Serious adverse events	60 participants	73 participants
Number of Participants With Adverse Events Serious adverse drug reactions	3 participants	6 participants
Number of Participants With Adverse Events SAEs leading to discontinuation of study drug	7 participants	12 participants
Number of Participants With Adverse Events Deaths	1 participants	3 participants

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 24, 36, and 52

Population: The intent-to-treat population includes all randomized participants. Five participants were excluded due to double enrollment at different sites.

Participants monitored their bowel movements and completed a daily bowel habits diary the week prior to study visits (i.e. during Weeks 11, 23, 35, and 51).

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Change From Baseline in the Number of Bowel Movements Per Week Week 52	3.92 bowel movements / week Standard Error 0.184	2.92 bowel movements / week Standard Error 0.187
Change From Baseline in the Number of Bowel Movements Per Week Week 12	3.70 bowel movements / week Standard Error 0.163	2.42 bowel movements / week Standard Error 0.162
Change From Baseline in the Number of Bowel Movements Per Week Week 24	3.77 bowel movements / week Standard Error 0.172	2.77 bowel movements / week Standard Error 0.172
Change From Baseline in the Number of Bowel Movements Per Week Week 36	3.88 bowel movements / week Standard Error 0.180	2.88 bowel movements / week Standard Error 0.177

SECONDARY outcome

Timeframe: From 28 days prior to screening until the end of the treatment period (total of 56 weeks)

Population: Intent-to-treat population

Participants who were taking stable routine/regular laxatives at Screening were to continue taking the same regimen throughout the study. The percentage of participants meeting each of the criteria below are reported: 1\. Participants not on stable laxatives, defined as participants who did not use laxatives from 28 days prior to the Screening Period to the final dose of study drug or who received only rescue laxative. Rescue is defined as any laxative taken for the first time during the Treatment Period. 1a. Out of participants who were not on stable laxatives, participants who received rescue laxatives. 2\. Participants on stable laxatives, defined as participants who may have had at least one/any stable laxative use reported from 28 days prior to Screening Period to the final dose of study drug. 2a. Out of participants who were on stable laxatives, participants who received rescue laxatives. 3\. Participants who did not meet criteria 1 or 2.

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Percentage of Participants Meeting Each Criterion of Laxative Use 1. Participants not on stable laxatives	30.0 percentage of participants	29.5 percentage of participants
Percentage of Participants Meeting Each Criterion of Laxative Use 1a. Who received rescue laxative	7.0 percentage of participants	13.1 percentage of participants
Percentage of Participants Meeting Each Criterion of Laxative Use 2. Participants on stable laxatives	50.2 percentage of participants	54.0 percentage of participants
Percentage of Participants Meeting Each Criterion of Laxative Use 2a. Who received rescue laxative	8.0 percentage of participants	14.0 percentage of participants
Percentage of Participants Meeting Each Criterion of Laxative Use 3. Other participants	19.8 percentage of participants	16.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 12, 24, 36, and 52

Population: The intent-to-treat population includes all randomized participants. Five participants were excluded due to double enrollment at different sites.

The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The overall score was calculated as the mean of all 12 items and ranges from 0 (best) to 4 (worst). A negative change from baseline value indicates improvement.

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms Week 2	-1.15 units on a scale Standard Error 0.036	-0.81 units on a scale Standard Error 0.036
Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms Week 12	-1.11 units on a scale Standard Error 0.039	-0.86 units on a scale Standard Error 0.039
Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms Week 24	-1.16 units on a scale Standard Error 0.039	-0.87 units on a scale Standard Error 0.039
Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms Week 36	-1.21 units on a scale Standard Error 0.040	-0.85 units on a scale Standard Error 0.040
Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms Week 52	-1.22 units on a scale Standard Error 0.041	-0.98 units on a scale Standard Error 0.042

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 12, 24, 36, and 52

Population: Intent-to-treat population

The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The abdominal-symptom domain score was calculated as the mean of the following 4 items: abdominal discomfort, abdominal pain, abdominal bloating and stomach cramps. A negative change from baseline value indicates improvement in symptoms.

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score Week 2	-0.99 units on a scale Standard Error 0.038	-0.79 units on a scale Standard Error 0.038
Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score Week 12	-0.93 units on a scale Standard Error 0.042	-0.78 units on a scale Standard Error 0.043
Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score Week 24	-0.99 units on a scale Standard Error 0.043	-0.81 units on a scale Standard Error 0.043
Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score Week 36	-1.06 units on a scale Standard Error 0.043	-0.78 units on a scale Standard Error 0.043
Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score Week 52	-1.07 units on a scale Standard Error 0.045	-0.94 units on a scale Standard Error 0.045

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 12, 24, 36, and 52

Population: Intent-to-treat population

The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The abdominal-symptom domain score was calculated as the mean of the following 3 items: painful bowel movements, rectal burning during or after a bowel movement, and rectal bleeding or tearing during or after a bowel movement. A negative change from baseline value indicates improvement in symptoms.

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score Week 2	-1.00 units on a scale Standard Error 0.040	-0.75 units on a scale Standard Error 0.040
Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score Week 12	-0.97 units on a scale Standard Error 0.044	-0.81 units on a scale Standard Error 0.045
Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score Week 24	-1.02 units on a scale Standard Error 0.046	-0.79 units on a scale Standard Error 0.046
Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score Week 36	-1.02 units on a scale Standard Error 0.045	-0.76 units on a scale Standard Error 0.045
Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score Week 52	-1.03 units on a scale Standard Error 0.046	-0.87 units on a scale Standard Error 0.047

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 12, 24, 36, and 52

Population: Intent-to-treat population

The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The stool-symptom domain score was calculated as the mean of the following 5 items: incomplete bowel movements, bowel movements that were too hard, bowel movements that were too small, straining or squeezing to try to pass bowel movements, and false-alarm bowel movements. A negative change from baseline value indicates improvement in symptoms.

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Change From Baseline in the PAC-SYM Stool-symptoms Domain Score Week 2	-1.37 units on a scale Standard Error 0.045	-0.86 units on a scale Standard Error 0.045
Change From Baseline in the PAC-SYM Stool-symptoms Domain Score Week 12	-1.34 units on a scale Standard Error 0.046	-0.96 units on a scale Standard Error 0.047
Change From Baseline in the PAC-SYM Stool-symptoms Domain Score Week 24	-1.37 units on a scale Standard Error 0.048	-0.97 units on a scale Standard Error 0.048
Change From Baseline in the PAC-SYM Stool-symptoms Domain Score Week 36	-1.44 units on a scale Standard Error 0.050	-0.96 units on a scale Standard Error 0.050
Change From Baseline in the PAC-SYM Stool-symptoms Domain Score Week 52	-1.45 units on a scale Standard Error 0.051	-1.08 units on a scale Standard Error 0.051

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 12, 24, 36, and 52

Population: Intent-to-treat

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score Week 12	-1.19 units on a scale Standard Error 0.036	-0.83 units on a scale Standard Error 0.037
Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score Week 2	-1.14 units on a scale Standard Error 0.033	-0.75 units on a scale Standard Error 0.033
Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score Week 24	-1.19 units on a scale Standard Error 0.038	-0.86 units on a scale Standard Error 0.038
Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score Week 36	-1.22 units on a scale Standard Error 0.039	-0.82 units on a scale Standard Error 0.039
Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score Week 52	-1.24 units on a scale Standard Error 0.039	-0.94 units on a scale Standard Error 0.040

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 12, 24, 36, and 52

Population: Intent-to-treat population

The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The physical discomfort domain consists of 4 questions related to bloating, feeling heavy, how much of the time participants felt any physical discomfort and how much time they felt the need to open their bowel but were not able to. The physical discomfort score was calculated as the mean of the 4 individual scores. A negative change from baseline value indicates improvement.

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Change From Baseline in the Physical Discomfort Domain of PAC-QOL Week 2	-1.33 units on a scale Standard Error 0.040	-0.94 units on a scale Standard Error 0.040
Change From Baseline in the Physical Discomfort Domain of PAC-QOL Week 12	-1.27 units on a scale Standard Error 0.044	-0.95 units on a scale Standard Error 0.045
Change From Baseline in the Physical Discomfort Domain of PAC-QOL Week 24	-1.26 units on a scale Standard Error 0.046	-0.98 units on a scale Standard Error 0.046
Change From Baseline in the Physical Discomfort Domain of PAC-QOL Week 36	-1.28 units on a scale Standard Error 0.048	-0.94 units on a scale Standard Error 0.048
Change From Baseline in the Physical Discomfort Domain of PAC-QOL Week 52	-1.38 units on a scale Standard Error 0.047	-1.09 units on a scale Standard Error 0.047

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 12, 24, 36, and 52

Population: Intent-to-treat population

The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The psychosocial discomfort domain consists of 8 questions related to participants' embarrassment regarding their constipation and effects of constipation on eating habits and appetite. The psychosocial discomfort score was calculated as the mean of the 8 individual scores. A negative change from baseline value indicates improvement.

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL Week 2	-0.92 units on a scale Standard Error 0.036	-0.69 units on a scale Standard Error 0.036
Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL Week 12	-0.96 units on a scale Standard Error 0.039	-0.72 units on a scale Standard Error 0.039
Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL Week 24	-0.97 units on a scale Standard Error 0.040	-0.72 units on a scale Standard Error 0.040
Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL Week 36	-0.99 units on a scale Standard Error 0.042	-0.68 units on a scale Standard Error 0.042
Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL Week 52	-1.00 units on a scale Standard Error 0.043	-0.80 units on a scale Standard Error 0.043

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 12, 24, 36, and 52

Population: Intent-to-treat population

The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The worries and concerns domain consists of 11 questions related to participants' feelings and concerns about their constipation. The worries and concerns domain score was calculated as the mean of the 11 individual scores. A negative change from baseline value indicates improvement.

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Change From Baseline in the Worries and Concerns Domain of PAC-QOL Week 2	-1.14 units on a scale Standard Error 0.038	-0.74 units on a scale Standard Error 0.038
Change From Baseline in the Worries and Concerns Domain of PAC-QOL Week 12	-1.21 units on a scale Standard Error 0.042	-0.85 units on a scale Standard Error 0.042
Change From Baseline in the Worries and Concerns Domain of PAC-QOL Week 24	-1.19 units on a scale Standard Error 0.043	-0.87 units on a scale Standard Error 0.043
Change From Baseline in the Worries and Concerns Domain of PAC-QOL Week 36	-1.23 units on a scale Standard Error 0.044	-0.81 units on a scale Standard Error 0.044
Change From Baseline in the Worries and Concerns Domain of PAC-QOL Week 52	-1.24 units on a scale Standard Error 0.045	-0.92 units on a scale Standard Error 0.045

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 12, 24, 36, and 52

Population: Intent-to-treat population

The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The satisfaction domain consists of 5 questions related to participants' feelings of satisfaction with their bowel function. The satisfaction domain score was calculated as the mean of the 5 individual scores. A negative change from baseline value indicates improvement.

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Change From Baseline in the Satisfaction Domain of PAC-QOL Week 2	-1.37 units on a scale Standard Error 0.050	-0.70 units on a scale Standard Error 0.050
Change From Baseline in the Satisfaction Domain of PAC-QOL Week 12	-1.45 units on a scale Standard Error 0.053	-0.87 units on a scale Standard Error 0.053
Change From Baseline in the Satisfaction Domain of PAC-QOL Week 24	-1.50 units on a scale Standard Error 0.054	-0.99 units on a scale Standard Error 0.054
Change From Baseline in the Satisfaction Domain of PAC-QOL Week 36	-1.53 units on a scale Standard Error 0.056	-1.00 units on a scale Standard Error 0.056
Change From Baseline in the Satisfaction Domain of PAC-QOL Week 52	-1.54 units on a scale Standard Error 0.059	-1.07 units on a scale Standard Error 0.059

SECONDARY outcome

Timeframe: Week 52 or early termination visit

Population: Intent-to-treat population

Participants were asked to rate their degree of satisfaction of constipation and abdominal symptoms from the start of study drug dosing to Week 52 (or early termination). Satisfaction was rated based on the following seven grades: * Grade 1 = markedly worsened * Grade 2 = moderately worsened * Grade 3 = slightly worsened * Grade 4 = unchanged * Grade 5 = slightly improved * Grade 6 = moderately improved * Grade 7 = markedly improved

Outcome measures

Outcome measures
Measure	Naldemedine n=621 Participants Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=620 Participants Participants received placebo tablets orally once daily for 52 weeks.
Participant Global Satisfaction Markedly worsened	2.4 percentage of participants	2.0 percentage of participants
Participant Global Satisfaction Moderately worsened	0.6 percentage of participants	2.8 percentage of participants
Participant Global Satisfaction Slightly worsened	1.0 percentage of participants	2.2 percentage of participants
Participant Global Satisfaction Unchanged	14.9 percentage of participants	33.5 percentage of participants
Participant Global Satisfaction Slightly improved	20.1 percentage of participants	23.0 percentage of participants
Participant Global Satisfaction Moderately improved	26.0 percentage of participants	17.7 percentage of participants
Participant Global Satisfaction Markedly improved	35.0 percentage of participants	18.8 percentage of participants

Adverse Events

Naldemedine

Serious events: 60 serious events

Other events: 225 other events

Deaths: 0 deaths

Placebo

Serious events: 73 serious events

Other events: 179 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Naldemedine n=621 participants at risk Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.	Placebo n=619 participants at risk Participants received placebo tablets orally once daily for 52 weeks.
Infections and infestations Upper Respiratory Tract Infection	5.8% 36/621 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.	5.3% 33/619 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.
Infections and infestations Urinary Tract Infection	6.1% 38/621 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.	8.2% 51/619 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.
Nervous system disorders Headache	4.5% 28/621 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.	5.3% 33/619 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.
Gastrointestinal disorders Abdominal Pain	8.1% 50/621 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.	2.9% 18/619 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.
Gastrointestinal disorders Vomiting	5.8% 36/621 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.	2.9% 18/619 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.
Gastrointestinal disorders Diarrhoea	11.0% 68/621 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.	5.3% 33/619 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.
Gastrointestinal disorders Nausea	7.9% 49/621 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.	5.7% 35/619 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.
Musculoskeletal and connective tissue disorders Back Pain	5.5% 34/621 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.	4.4% 27/619 • From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). The safety population included all participants who were randomized and received at least 1 dose of study drug and were analyzed by the treatment actually received. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.

Additional Information

Shionogi Clinical Trials Administrator

Shionogi Inc.

Phone: 800-849-9707

Email: [email protected]

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