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Long Term Safety of Naldemedine

Primary Purpose

Opioid-induced Constipation

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Naldemedine

Placebo

About this trial

This is an interventional treatment trial for Opioid-induced Constipation focused on measuring Opioid Induced Constipation

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

Subjects aged 18 to 80 years inclusive at the time of informed consent
Subjects must have non-malignant chronic pain treated and must have opioid induced constipation (OIC)
Subjects must be treated with a stable opioid regimen at a total daily dose on average of ≥ 30 mg equivalents of oral morphine sulfate
Subjects may or may not be on a routine laxative regimen at the time of Screening

Exclusion Criteria

Evidence of significant structural abnormalities of the gastrointestinal (GI) tract
Evidence of active medical diseases affecting bowel transit
History of pelvic disorders that may be a cause of constipation
Surgery (except for minor procedures) within 60 days of Screening
History of chronic constipation prior to starting analgesic medication or any potential non-opioid cause of bowel dysfunction that may be a major contributor to the constipation (e.g. mechanical GI obstruction)
Subjects who have never taken laxatives for the treatment of OIC
Current use of any prohibited medication including opioid antagonists, partial or mixed agonists/antagonists

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Naldemedine

Placebo

Arm Description

Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.

Participants received matching placebo tablets orally once daily for 52 weeks.

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events

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.

Secondary Outcome Measures

Change From Baseline in the Number of Bowel Movements Per Week

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).

Percentage of Participants Meeting Each Criterion of Laxative Use

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.

Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms

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.

Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score

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.

Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score

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.

Change From Baseline in the PAC-SYM Stool-symptoms Domain Score

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.

Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score

Change From Baseline in the Physical Discomfort Domain of PAC-QOL

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.

Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL

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.

Change From Baseline in the Worries and Concerns Domain of PAC-QOL

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.

Change From Baseline in the Satisfaction Domain of PAC-QOL

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.

Participant Global Satisfaction

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

Full Information

NCT ID

NCT01965652

First Posted

October 15, 2013

Last Updated

April 16, 2018

Sponsor

Shionogi

1. Study Identification

Unique Protocol Identification Number

NCT01965652

Brief Title

Long Term Safety of Naldemedine

Official Title

A Randomized Double-blind, Placebo-controlled, Parallel-group, Multicenter, Phase 3 Study to Evaluate the Long-term Safety of Naldemedine for the Treatment of Opioid-induced Constipation in Subjects With Non-malignant Chronic Pain Receiving Opioid Therapy

Study Type

Interventional

2. Study Status

Record Verification Date

April 2018

Overall Recruitment Status

Completed

Study Start Date

September 24, 2013 (Actual)

Primary Completion Date

January 12, 2016 (Actual)

Study Completion Date

January 12, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Shionogi

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to evaluate the long-term safety of naldemedine for the treatment of constipation due to opioid therapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Opioid-induced Constipation

Keywords

Opioid Induced Constipation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

1246 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Naldemedine

Arm Type

Experimental

Arm Description

Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Participants received matching placebo tablets orally once daily for 52 weeks.

Intervention Type

Drug

Intervention Name(s)

Naldemedine

Other Intervention Name(s)

S-297995, Symproic®

Intervention Description

Naldemedine 0.2 mg tablet taken orally once a day

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo tablet taken orally once a day

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events

Description

Time Frame

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

Secondary Outcome Measure Information:

Title

Change From Baseline in the Number of Bowel Movements Per Week

Description

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).

Time Frame

Baseline and Weeks 12, 24, 36, and 52

Title

Percentage of Participants Meeting Each Criterion of Laxative Use

Description

Time Frame

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

Title

Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms

Description

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.

Time Frame