A Study of Naldemedine (S-297995) for the Treatment of Opioid-Induced Constipation in Adults With Non-Malignant Chronic Pain Receiving Opioid Therapy

Study Overview
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Brief Summary
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The purpose of this study is to determine efficacy and safety of naldemedine for the treatment of opioid-induced constipation in adults with non-malignant chronic pain receiving opioid therapy for ≥ 3 months.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of S-297995 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: Placebo
* Drug: Naldemedine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects aged 18 years or older at time of informed consent with non-malignant chronic pain experiencing opioid-induced constipation Subjects with < 3 spontaneous bowel movements a week and experiencing bowel symptoms Subjects receiving chronic opioid therapy due to non-malignant pain for ≥ 3 months Exclusion Criteria: Evidence of clinically significant gastrointestinal disease 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 Severe constipation that has not been appropriately managed such that the subject is at immediate risk of developing serious complications of constipation

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received placebo orally once daily for 28 days. | Drug: Placebo<br>* Matching placebo tablets administered orally once a day.<br>|
| Experimental: Naldemedine 0.1 mg<br>Participants received 0.1 mg naldemedine orally once daily for 28 days. | Drug: Naldemedine<br>* Naldemedine tablets administered orally once a day.<br>* Other names: Symproic®;|
| Experimental: Naldemedine 0.2 mg<br>Participants received 0.2 mg naldemedine orally once daily for 28 days. | Drug: Naldemedine<br>* Naldemedine tablets administered orally once a day.<br>* Other names: Symproic®;|
| Experimental: Naldemedine 0.4 mg<br>Participants received 0.4 mg naldemedine orally once daily for 28 days. | Drug: Naldemedine<br>* Naldemedine tablets administered orally once a day.<br>* Other names: Symproic®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per week during the 2 weeks prior to randomization. The number of SBMs per week in the last 2 weeks of treatment is defined as the average number of SBMs per week recorded in the diary for the 14 days prior to the last dose of study drug. | Baseline (2 weeks prior to randomization) and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Spontaneous Bowel Movements Per Week | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per day during the 2 weeks prior to randomization. | Baseline and Weeks 1, 2, 3, and 4 | 
| Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Bowel Movements (BMs) Per Week | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A BM was defined as all bowel movements observed irrespective of the use of a laxative agent. | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Bowel Movements Per Week | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A BM was defined as all bowel movements observed irrespective of the use of a laxative agent. | Baseline and Weeks 1, 2, 3, and 4 | 
| Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Bowel Movements (CBMs) Per Week | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A complete BM (CBM) was defined as a BM where the participant answered 'Yes' to the following question: 'Did you have a feeling of complete emptying after the bowel movement?' | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Bowel Movements Per Week | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A complete BM (CBM) was defined as a BM where the participant answered 'Yes' to the following question: 'Did you have a feeling of complete emptying after the bowel movement?' | Baseline and Weeks 1, 2, 3, and 4 | 
| Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements (CSBMs) Per Week | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation. | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Spontaneous Bowel Movements Per Week | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation. | Baseline and Weeks 1, 2, 3, and 4 | 
| Percentage of Participants With an SBM Response in the Last 2 Weeks of the Treatment Period | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. An SBM responder was defined as a participant whose frequency of SBMs within the last 2 weeks of the treatment period was 3 times or more per week and who had an average increase in the frequency of SBMs from baseline of 1 or more per week. | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. An SBM responder was defined as any participant whose frequency of SBM per week during the treatment period was 3 times or more per week, and who had an average increase from baseline of 1 or more per week. | Baseline and Weeks 1, 2, 3, and 4 | 
| Percentage of Participants With a CSBM Response in the Last 2 Weeks of the Treatment Period | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM responder was defined as a participant whose frequency of CSBMs within the last 2 weeks of the treatment period was 3 times or more per week and who had an average increase in the frequency of CSBMs from baseline of 1 or more per week. | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM responder was defined as a participant whose frequency of CSBMs during the treatment period was 3 times or more per week and who had an average increase in the frequency of CSBMs from baseline of 1 or more per week. | Baseline and Weeks 1, 2, 3, and 4 | 
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With SBMs | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. An SBM is defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement. | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With SBMs | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. An SBM is defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement. | Baseline and Weeks 1, 2, 3, and 4 | 
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With CSBMs | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation. | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With CSBMs | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation. | Baseline and Weeks 1, 2, 3, and 4 | 
| Time to the First Spontaneous Bowel Movement | Time to the first SBM was defined as the time to the first SBM after the initial administration of study drug. Participants who withdrew from the study before an SBM was observed or had no SBM during the treatment period were treated as censored. | 28 days | 
| Time to the First Complete Spontaneous Bowel Movement | Time to the first CSBM was defined as the time to the first CSBM after the initial administration of study drug. Participants who withdrew from the study before a CSBM was observed or had no CSBM during the treatment period were treated as censored. | 28 days | 
| Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | The percentage of participants who experienced at least one SBM within 4, 8, 12, and 24 hours after the initial administration of study drug and before the second administration. | 4, 8, 12, and 24 hours | 
| Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | The percentage of participants who experienced at least one CSBM within 4, 8, 12, and 24 hours after the initial administration of study drug and before the second administration. | 4, 8, 12, and 24 hours | 
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week Rated as 3 or 4 on the Bristol Stool Scale | Consistency of BMs was measured using the Bristol Stool Scale, according to the following: 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 and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Change From Baseline to Weeks 1, 2, 3, and 4 in Number of SBMs Rated as 3 or 4 on the Bristol Stool Scale Per Week | Consistency of BMs was measured using the Bristol Stool Scale, according to the following: 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 and Weeks 1, 2, 3, and 4 | 
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week With no Straining | Straining during BMs was graded using the following scale: 0 = No straining; 1 = Mild straining; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining was defined as a BM with a straining score of 0 or 1. | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of SBMs Per Week Without Straining | Straining during BMs was graded using the following scale: 0 = No straining; 1 = Mild straining; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining is defined as a BM with a straining score of 0 or 1. | Baseline and Weeks 1, 2, 3, and 4 | 
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of False Start BMs Per Week | Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A false start was defined as any attempted, but unsuccessful bowel movement (no solid or liquid fecal material was excreted). | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Rescue Use of Laxative Agents Per Week | Participants were asked how many doses of rescue laxative medication they had taken within the past 24 hours as part of the Bowel Movement and Constipation Assessment Diary (BMCA). | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Mean Rescue Laxative Use Per Week During the Treatment Period | Participants were asked how many doses of rescue laxative medication they had taken within the past 24 hours as part of the Bowel Movement and Constipation Assessment Diary (BMCA). | Weeks 1 to 4 | 
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Bloating | Participants were asked to rate their abdominal bloating for the past 24 hours on a scale of 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Participants were asked to rate their abdominal bloating for the past 24 hours on a scale of 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. | Baseline and Weeks 1, 2, 3, and 4 | 
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Discomfort | Participants were asked to rate their abdominal discomfort for the past 24 hours on a scale from 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 
| Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Participants were asked to rate their abdominal discomfort for the past 24 hours on a scale from 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. | Baseline and Weeks 1, 2, 3, and 4 | 
| Subject Global Satisfaction at End of Treatment | On day 29 (or at early termination), participants were asked about their degree of satisfaction with constipation and abdominal symptoms from the start of study drug dosing to Day 28 (or early termination visit). The grades were as follows: 1, markedly worsened; 2, moderately worsened; 3, slightly worsened; 4, unchanged; 5, slightly improved; 6, moderately improved; and 7, markedly improved. | Day 29, or at early termination | 
| Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28. | Day 1 and Day 28 predose and 1, 2, 4, 8, and 24 hours postdose | 
| Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28. | Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose | 
| Area Under the Concentration-time Curve From Hour 0 to the Time Point of the Last Measurable Concentration Within the Dose Interval (AUC0-τ) | Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28. | Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-emergent adverse events (TEAEs) were adverse events that occurred after the first dose of study drug. Treatment-related TEAEs were defined as TEAEs that were considered by the Investigator to be definitely, probably, or possibly related to study drug. | From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opioid Therapy, Non-Malignant Chronic Pain, Opioid-Induced Constipation