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

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

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.

Study Overview

• Status: Completed
• Conditions: Opioid-induced Constipation
• Intervention / Treatment: Drug: Placebo; Drug: Naldemedine

• Study Type: Interventional
• Enrollment (Actual): 244
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States
      • Shionogi Research Site
    • Sun Lakes, Arizona, United States
      • Shionogi Research Site
  • Arkansas
    • Little Rock, Arkansas, United States
      • Shionogi Research Site
  • California
    • Anaheim, California, United States
      • Shionogi Research Site
    • Fresno, California, United States
      • Shionogi Research Site
    • Lincoln, California, United States
      • Shionogi Research Site
    • Lomita, California, United States
      • Shionogi Research Site
  • Colorado
    • Denver, Colorado, United States
      • Shionogi Research Site
  • Florida
    • Brandon, Florida, United States
      • Shionogi Research Site
    • Kissimmee, Florida, United States
      • Shionogi Research Site
    • New Port Richey, Florida, United States
      • Shionogi Research Site
    • North Miami, Florida, United States
      • Shionogi Research Site
    • Ocala, Florida, United States
      • Shionogi Research Site
    • Orlando, Florida, United States
      • Shionogi Research Site
    • Ormond Beach, Florida, United States
      • Shionogi Research Site
    • Port Orange, Florida, United States
      • Shionogi Research Site
    • Sarasota, Florida, United States
      • Shionogi Research Site
    • South Miami, Florida, United States
      • Shionogi Research Site
    • West Palm Beach, Florida, United States
      • Shionogi Research Site
  • Georgia
    • Atlanta, Georgia, United States
      • Shionogi Research Site
    • Decatur, Georgia, United States
      • Shionogi Research Site
    • Marietta, Georgia, United States
      • Shionogi Research Site
  • Indiana
    • Evansville, Indiana, United States
      • Shionogi Research Site
  • Kentucky
    • Lexington, Kentucky, United States
      • Shionogi Research Site
  • Louisiana
    • Shreveport, Louisiana, United States
      • Shionogi Research Site
  • Maryland
    • Owings Mills, Maryland, United States
      • Shionogi Research Site
  • Massachusetts
    • Watertown, Massachusetts, United States
      • Shionogi Research Site
    • Worcester, Massachusetts, United States
      • Shionogi Research Site
  • Michigan
    • Traverse City, Michigan, United States
      • Shionogi Research Site
  • Minnesota
    • Edina, Minnesota, United States
      • Shionogi Research Site
  • Nevada
    • Las Vegas, Nevada, United States
      • Shionogi Research Site
  • New Hampshire
    • Newington, New Hampshire, United States
      • Shionogi Research Site
  • New Jersey
    • Berlin, New Jersey, United States
      • Shionogi Research Site
    • Willingboro, New Jersey, United States
      • Shionogi Research Site
  • New York
    • Hartsdale, New York, United States
      • Shionogi Research Site
    • North Syracuse, New York, United States
      • Shionogi Research Site
    • Williamsville, New York, United States
      • Shionogi Research Site
  • North Carolina
    • Wilmington, North Carolina, United States
      • Shionogi Research Site
    • Winston-Salem, North Carolina, United States
      • Shionogi Research Site
  • Ohio
    • Canton, Ohio, United States
      • Shionogi Research Site
    • Columbus, Ohio, United States
      • Shionogi Research Site
    • Perrysburg, Ohio, United States
      • Shionogi Research Site
  • Oregon
    • Eugene, Oregon, United States
      • Shionogi Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Shionogi Research Site
  • South Carolina
    • Greer, South Carolina, United States
      • Shionogi Research Site
  • Texas
    • Austin, Texas, United States
      • Shionogi Research Site
    • Dallas, Texas, United States
      • Shionogi Research Site
  • Utah
    • Orem, Utah, United States
      • Shionogi Research Site
    • Salt Lake City, Utah, United States
      • Shionogi Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Participants received placebo orally once daily for 28 days.	Drug: Placebo; Matching placebo tablets administered orally once a day.
EXPERIMENTAL: Naldemedine 0.1 mg; Participants received 0.1 mg naldemedine orally once daily for 28 days.	Drug: Naldemedine; Naldemedine tablets administered orally once a day.; Other Names: Symproic®; S 297995
EXPERIMENTAL: Naldemedine 0.2 mg; Participants received 0.2 mg naldemedine orally once daily for 28 days.	Drug: Naldemedine; Naldemedine tablets administered orally once a day.; Other Names: Symproic®; S 297995
EXPERIMENTAL: Naldemedine 0.4 mg; Participants received 0.4 mg naldemedine orally once daily for 28 days.	Drug: Naldemedine; Naldemedine tablets administered orally once a day.; Other Names: Symproic®; S 297995

What is the study measuring?

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).

Collaborators and Investigators

• Sponsor: Shionogi

Publications and helpful links

General Publications

• Webster LR, Yamada T, Arjona Ferreira JC. A Phase 2b, Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Efficacy and Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain. Pain Med. 2017 Dec 1;18(12):2350-2360. doi: 10.1093/pm/pnw325.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 17, 2011
• Primary Completion (ACTUAL): August 22, 2012
• Study Completion (ACTUAL): August 22, 2012

Study Registration Dates

• First Submitted: September 20, 2011
• First Submitted That Met QC Criteria: September 27, 2011
• First Posted (ESTIMATE): September 29, 2011

Study Record Updates

• Last Update Posted (ACTUAL): June 26, 2017
• Last Update Submitted That Met QC Criteria: May 31, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Opioid-Induced Constipation; Opioid Therapy; Non-Malignant Chronic Pain
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Pain; Neurologic Manifestations; Signs and Symptoms, Digestive; Narcotic-Related Disorders; Chronic Pain; Constipation; Opioid-Induced Constipation
• Other Study ID Numbers: 1107V9221