Severity of adverse events (AEs) was graded according to the following definitions:

• Mild: The subject experiences awareness of symptoms but these are easily tolerated or managed without specific treatment
• Moderate: The subject experiences discomfort enough to cause interference with usual activity, and/or the condition requires specific treatment
• Severe: The subject is incapacitated with inability to work or do usual activity, and/or the event requires significant treatment measures.

The relationship of the event to the study drug was determined by the investigator.

A serious adverse event (SAE) is defined as any AE occurring at any dose 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.

All participants who received any amount of study drug (safety population).

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used in the 24 hours preceding the bowel movement.

Baseline was defined as the average number of SBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15).

All randomized participants who received study drug and had at least 1 post-dose efficacy assessment completed (intent-to-treat population). Last observation carried forward (LOCF) imputation was used.

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used in the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of SBMs per day from 0 to 48 hours post-dose.

Intent-to-treat population; LOCF imputation was used

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. Baseline was defined as the average number of BMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15).

Intent-to-treat; LOCF imputation was used

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. Baseline was defined as the average number of BMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of BMs per day from 0 to 48 hours post-dose.

Intent-to-treat population; LOCF imputation was used

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A complete spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used and the bowel movement resulted in a sensation of complete evacuation (based on the question of "having a feeling of complete emptying after the bowel movement").

Baseline was defined as the average number of CSBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15).

Intent-to-treat population; LOCF imputation was used

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A complete spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used and the bowel movement resulted in a sensation of complete evacuation (based on the question of "having a feeling of complete emptying after the bowel movement").

Baseline was defined as the average number of CSBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of CSBMs per day from 0 to 48 hours post-dose.

Intent-to-treat population; LOCF imputation was used

The time to first SBM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first SBM was counted as an event and the time to first SBM after dosing was calculated from the date and time of first dosing until the date and time of first SBM. Participants who dropped out or were lost to follow-up before the first SBM were censored.

Intent-to-treat population

The time to first BM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first BM was counted as an event and the time to first BM after dosing was calculated from the date and time of first dosing until the date and time of first BM. Participants who dropped out or were lost to follow-up before the first BM were censored.

Intent-to-treat population

The time to first CSBM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first CSBM was counted as an event and the time to first CSBM after dosing was calculated from the date and time of first dosing until the date and time of first CSBM. Participants who dropped out or were lost to follow-up before the first CSBM were censored.

Intent-to-treat population

Straining during BMs was graded using the following scale: 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.

Baseline was defined as the average straining score of all BMs prior to receiving study drug (Day 1 to Day 15). The straining score at 24 and 48 hours post-dose was calculated as the average straining score from all bowel movements from 0 to 24 and 0 to 48 hours post-dose, respectively.

Intent-to-treat population with available data at each time point

A complete bowel movement (CBM) was defined as a bowel movement that resulted in a sensation of complete evacuation based on the question "Did you have a feeling of complete emptying after the bowel movement?" Baseline was defined as the average number of CBMs per day prior to receiving study drug (Day 1 to Day 15).

Intent-to-treat population; LOCF imputation was used

A complete bowel movement (CBM) was defined as a bowel movement that resulted in a sensation of complete evacuation based on the question "Did you have a feeling of complete emptying after the bowel movement?" Baseline was defined as the average number of CBMs per day prior to receiving study drug (Day 1 to 15). Forty-eight hours post-dose was calculated as the average number of CBMs per day from 0 to 48 hours post-dose.

Intent-to-treat population; LOCF imputation was used

Participants were asked to rate their abdominal bloating for the past 24 hours using the following scale:

0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. Baseline was defined as the average abdominal bloating score prior to receiving study drug (Day 1 to Day 15). Abdominal bloating at 24 hours and 48 hours post-dose was calculated as the mean score from 0 to 24 and 0 to 48 hours post-dose respectively.

Intent-to-treat population with available data at each time point.

Participants were asked to rate their abdominal discomfort for the past 24 hours using the following scale:

0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. Baseline was defined as the average abdominal discomfort score prior to receiving study drug (Day 1 to Day 15). Abdominal discomfort at 24 hours and 48 hours post-dose was calculated as the mean score from 0 to 24 and 0 to 48 hours post-dose respectively.

Intent-to-treat population with available data at each time point.

Consistency of BMs was measured using the Bristol Stool Scale, as follows:

1 = separate hard lumps like nuts; 2 = sausage shaped but lumpy; 3 = like a sausage, but with cracks on its surface; 4 = like a sausage or a snake, smooth and soft; 5 = soft blobs and with clear-cut edges; 6 = floppy pieces with ragged edges/mushy stool; 7 = watery, no solid pieces, entirely liquid.

Baseline was defined as the average consistency of BMs prior to receiving study drug (Day 1 to Day 15). BM consistency at 24 hours and 48 hours post-dose was calculated as the average scores from all bowel movements from 0 to 24 and 0 to 48 hours post-dose, respectively.

Intent-to-treat population with available data at each time point.

A false start was defined as any attempted, but unsuccessful bowel movement (no solid or liquid fecal material was excreted) based on the question "In the past 24 hours, how many times did you try to have a bowel movement but were unsuccessful?" Baseline was defined as the average number of false start BMs per day prior to receiving study drug (Day 1 to Day 15).

The number of false start BMs per day at 24 hours and 48 hours post-dose was calculated as is the average number of false start BMs per day from 0 to 24 and 0 to 48 hours post-dose, respectively.

Intent-to-treat population; LOCF imputation was used

Straining during BMs was graded using the following scale:

0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining was defined as a BM with a straining score = 0.

Baseline was defined as the average number of BMs without straining per day prior to receiving study drug (Day 1 to Day 15). The number of BMs without straining per day at 24 hours and 48 hours post-dose was calculated as the average number of BMs with no straining per day from 0 to 24 hours and 0 to 48 hours post-dose, respectively.

Intent-to-treat population; LOCF imputation was used

Baseline was defined as the average number of rescue medications used per day prior to receiving study drug (Day 1 to Day 15). The number of rescue medications used per day at 24 hours and 48 hours post-dose was calculated as the average number of rescue medications used per day from 0 to 24 hours and 0 to 48 hours post-dose, respectively.

Intent-to-treat population; LOCF imputation was used

The COWS assessment consisted of 11 questions which rated the severity of opiate withdrawal symptoms, including resting pulse rate, gastrointestinal upset, sweating, restlessness, pupil size, tremor, anxiety or irritability, bone or joint aches, gooseflesh skin, yawning, and runny nose or tearing. Each symptom was rated on a scale from 0 (not present) to 4 or 5 (most severe). The total score was calculated by summing the 11 individual scores and ranged from 0 (no withdrawal symptoms) to 48 (worst symptoms).

Safety population

The Webster Opiate Withdrawal Scale (WOWS) assessment consisted of 7 questions which rate the severity of opiate withdrawal symptoms, including sweating, sleep, bone or joint aches, runny nose or tearing, gastrointestinal upset, anxiety or irritability and gooseflesh skin. Each symptom was rated on a scale from 0 (not present/no issues) to 4 or 5 (severe). The total score was calculated by summing the 7 individual scores and ranged from 0 (no withdrawal symptoms) to 29 (worst symptoms).

Safety population

The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method.

The pharmacokinetic (PK) analysis population included all randomized participants who received study drug and had at least one post-dose PK assessment completed.

The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method.

PK population

The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Area under the plasma concentration versus time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantitation, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations (Linear Up/ Log Down).

PK population

The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Area under the plasma concentration versus time curve from time zero to infinity, calculated using the formula: AUC0-inf = AUC0-t + Ct/λZ where Ct was the last measurable concentration and λZ was the apparent terminal elimination rate constant.

PK population

The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. The apparent elimination half-life was calculated using the formula t1/2,z = (ln2)/λZ

PK population