Study to Evaluate the Safety and Efficacy of Naldemedine (S-297995) for the Treatment of Opioid-Induced Bowel Dysfunction in Subjects With Chronic Pain

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the safety of single doses of oral naldemedine in adults physically dependent on opioids.

Detailed Description
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A single dose of naldemedine or matching placebo will be administered orally to each cohort of 12 participants (9 treatments, 3 placebos) in the morning of Day 15 under fasted conditions. The first cohort will receive a 0.1 mg dose. Cohorts will continue to be enrolled at the next higher dose level until the highest dose level (3 mg) has been achieved or until the study is discontinued due to adverse events or Clinical Opioid Withdrawal Score of >8. A 0.03 mg dose will also be tested. A 0.01 mg dose will be tested if 4 or more subjects experience 1 or more bowel movements within the 24 hour period post dose in the 0.03 mg dosing cohort.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Single-Ascending Dose Study to Evaluate the Safety and Efficacy of S-297995 for the Treatment of Opioid-Induced Bowel Dysfunction in Subjects With Chronic Pain

Conditions
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Opioid Induced Bowel Dysfunction

Intervention / Treatment
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* Drug: Naldemedine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Understand and sign an informed consent form Males will agree to use an approved double-barrier method of contraception from Day 1 until 1 month after study completion Subject tests negative on urine drug test unless the subject has a prescription for the drug(s) that test positive Exclusion Criteria: Subjects under opioid therapy for cancer-related pain or for the management of drug addiction Fecal incontinence, irritable bowel syndrome, inflammatory bowel disease, or other active medical disorders associated with diarrhea, intermittent loose stools, or constipation Subjects who have participated in any other investigational drug study within 30 days prior to Day 1 Prior exposure to S-297995

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Single Group Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>In this cohort 9 participants received one 0.1 mg naldemedine tablet and 3 participants received matching placebo administered on Day 15 under fasted conditions. | Drug: Naldemedine<br>* Tablets or solution for oral administration<br>* Other names: Symproic®;Drug: Placebo<br>* Tablets or solution for oral administration<br>|
| Experimental: Cohort 2<br>In this cohort 9 participants received a single dose of 0.3 mg naldemedine tablets and 3 participants received matching placebo tablets administered on Day 15 under fasted conditions. | Drug: Naldemedine<br>* Tablets or solution for oral administration<br>* Other names: Symproic®;Drug: Placebo<br>* Tablets or solution for oral administration<br>|
| Experimental: Cohort 3<br>In this cohort 9 participants received a single dose of 1 mg naldemedine tablets and 3 participants received matching placebo tablets administered on Day 15 under fasted conditions. | Drug: Naldemedine<br>* Tablets or solution for oral administration<br>* Other names: Symproic®;Drug: Placebo<br>* Tablets or solution for oral administration<br>|
| Experimental: Cohort 4<br>In this cohort 9 participants received a single dose of 3 mg naldemedine tablets and 3 participants received matching placebo tablets administered on Day 15 under fasted conditions. | Drug: Naldemedine<br>* Tablets or solution for oral administration<br>* Other names: Symproic®;Drug: Placebo<br>* Tablets or solution for oral administration<br>|
| Experimental: Cohort 5<br>In this cohort 9 participants received a single dose of 0.03 mg naldemedine oral solution and 3 participants received matching placebo oral solution administered on Day 15 under fasted conditions. | Drug: Naldemedine<br>* Tablets or solution for oral administration<br>* Other names: Symproic®;Drug: Placebo<br>* Tablets or solution for oral administration<br>|
| Experimental: Cohort 6<br>In this cohort 9 participants received a single dose of 0.01 mg naldemedine oral solution and 3 participants received matching placebo oral solution administered on Day 15 under fasted conditions. | Drug: Naldemedine<br>* Tablets or solution for oral administration<br>* Other names: Symproic®;Drug: Placebo<br>* Tablets or solution for oral administration<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 | 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. | From the first dose of study drug on Day 15 up to Day 24. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | 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). | Baseline (Day 1 to Day 15) and Day 15 to 16 (0 to 24 hours post-dose) | 
| Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | 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. | Baseline (Day 1 to Day 15) and Day 15 to Day 17 (0 to 48 hours post-dose) | 
| Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | 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). | Baseline and 24 hours post-dose | 
| Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | 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. | Baseline and 48 hours post-dose | 
| Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 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). | Baseline and 24 hours post-dose | 
| Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 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. | Baseline and 48 hours post-dose | 
| Time to First Spontaneous Bowel Movement | 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. | From first dose on Day 15 through Day 17 | 
| Time to First Bowel Movement | 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. | From first dose on Day 15 through Day 17 | 
| Time to First Complete Spontaneous Bowel Movement | 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. | From first dose on Day 15 through Day 17 | 
| Change From Baseline in Straining During Bowel Movements | 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. | Baseline, 24 hours post-dose and 48 hours post-dose | 
| Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | 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). | Baseline and 24 hours post-dose | 
| Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | 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. | Baseline and 48 hours post-dose | 
| Change From Baseline in Abdominal Bloating | 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. | Baseline, 24 hours post-dose and 48 hours post-dose | 
| Change From Baseline in Abdominal Discomfort | 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. | Baseline, 24 hours post-dose and 48 hours post-dose | 
| Change From Baseline in BM Consistency | 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. | Baseline, 24 hours post-dose and 48 hours post-dose | 
| Change From Baseline in Number of False Start Bowel Movements Per Day | 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. | Baseline, 24 hours post-dose and 48 hours post-dose | 
| Change From Baseline in the Number of Bowel Movements With No Straining Per Day | 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. | Baseline, 24 hours post-dose and 48 hours post-dose | 
| Change From Baseline in Number of Rescue Medications Used Per Day | 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. | Baseline, 24 hours post-dose and 48 hours post-dose | 
| Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study | 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). | The COWS assessments were performed at Screening, on Day 14, Day 15 (pre-dose and 1, 2, 3, 4, 5, 6 and 8 hours post-dose, and at unscheduled times as signs or symptoms indicate), on Days 16 and 17, and on Day 24/End of Study. | 
| Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study | 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). | The WOWS assessment was performed at Screening, Day 14, Day 15 at pre-dose , and 24 and 48 hours post-dose and at the Follow-up/End of Study visit (Day 24). | 
| Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. | Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose. | 
| Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. | Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose. | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | 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). | Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose. | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | 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. | Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose. | 
| Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | 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 | Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic pain, Opioid physical dependence