Long Term Safety of Naldemedine

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

Official Title
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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

Conditions
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Opioid-induced Constipation

Intervention / Treatment
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* Drug: Naldemedine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Naldemedine<br>Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks. | Drug: Naldemedine<br>* Naldemedine 0.2 mg tablet taken orally once a day<br>* Other names: Symproic®;|
| Placebo Comparator: Placebo<br>Participants received matching placebo tablets orally once daily for 52 weeks. | Drug: Placebo<br>* Placebo tablet taken orally once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline and Weeks 12, 24, 36, and 52 | 
| 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. | From 28 days prior to screening until the end of the treatment period (total of 56 weeks) | 
| 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. | Baseline and Weeks 2, 12, 24, 36, and 52 | 
| 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. | Baseline and Weeks 2, 12, 24, 36, and 52 | 
| 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. | Baseline and Weeks 2, 12, 24, 36, and 52 | 
| 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. | Baseline and Weeks 2, 12, 24, 36, and 52 | 
| Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | 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 overall score was calculated as the mean of all 28 item scores. A negative change from baseline value indicates improvement. | Baseline and Weeks 2, 12, 24, 36, and 52 | 
| 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. | Baseline and Weeks 2, 12, 24, 36, and 52 | 
| 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. | Baseline and Weeks 2, 12, 24, 36, and 52 | 
| 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. | Baseline and Weeks 2, 12, 24, 36, and 52 | 
| 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. | Baseline and Weeks 2, 12, 24, 36, and 52 | 
| 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 | Week 52 or early termination visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opioid Induced Constipation