Efficacy and Safety of Naldemedine in the Treatment of Opioid-induced Constipation

A Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Naldemedine in the Treatment of Opioid-induced Constipation in Subjects With Non-malignant Chronic Pain Receiving Opioid Therapy

The purpose of this study is to evaluate the efficacy and safety of naldemedine in the treatment of opioid-induced constipation (OIC) in adults with non-malignant chronic pain who are not using laxatives.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 547
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • St. Poelten, Austria
    • Shionogi Research Site
  • Vienna, Austria
    • Shionogi Research Site
• Czechia
  • Hradec Kralove, Czechia
    • Shionogi Research Site
  • Liberec, Czechia
    • Shionogi Research Site
  • Pardubice, Czechia
    • Shionogi Research Site
  • Prague, Czechia
    • Shionogi Research Site
  • Vysoke Myto, Czechia
    • Shionogi Research Site
• Germany
  • Berlin, Germany
    • Shionogi Research Site
  • Eichstaett, Germany
    • Shionogi Research Site
  • Frankfurt am Main, Germany
    • Shionogi Research Site
• Poland
  • Bialystok, Poland
    • Shionogi Research Site
  • Bydgoszcz, Poland
    • Shionogi Research Site
  • Czeladź, Poland
    • Shionogi Research Site
  • Gorzów Wielkopolski, Poland
    • Shionogi Research Site
  • Warszawa, Poland
    • Shionogi Research Site
• Spain
  • Alicante, Spain
    • Shionogi Research Site
  • Cádiz, Spain
    • Shionogi Research Site
  • Madrid, Spain
    • Shionogi Research Site
• United Kingdom
  • Belfast, United Kingdom
    • Shionogi Research Site
  • Bexhill-on-Sea East Sussex, United Kingdom
    • Shionogi Research Site
  • Crownhill Plymouth, United Kingdom
    • Shionogi Research Site
  • Fowey Cornwall, United Kingdom
    • Shionogi Research Site
  • Liskeard Cornwall, United Kingdom
    • Shionogi Research Site
  • London, United Kingdom
    • Shionogi Research Site
  • Penzance Cornwall, United Kingdom
    • Shionogi Research Site
  • Soham Ely Cambs, United Kingdom
    • Shionogi Research Site
  • St Austell Cornwall, United Kingdom
    • Shionogi Research Site
  • Tomairt, United Kingdom
    • Shionogi Research Site
• United States
  • Alabama
    • Birmingham, Alabama, United States
      • Shionogi Research Site
  • Arizona
    • Phoenix, Arizona, United States
      • Shionogi Research Site
  • California
    • Fresno, California, United States
      • Shionogi Research Site
    • Long Beach, California, United States
      • Shionogi Research Site
    • National City, California, United States
      • Shionogi Research Site
    • North Hollywood, California, United States
      • Shionogi Research Site
    • Oceanside, California, United States
      • Shionogi Research Site
  • Colorado
    • Golden, Colorado, United States
      • Shionogi Research Site
  • Florida
    • Miami, Florida, United States
      • Shionogi Research Site
    • Miami Springs, Florida, United States
      • Shionogi Research Site
    • Orlando, Florida, United States
      • Shionogi Research Site
    • Sarasota, Florida, United States
      • Shionogi Research Site
    • West Palm Beach, Florida, United States
      • Shionogi Research Site
    • Winter Park, Florida, United States
      • Shionogi Research Site
  • Georgia
    • Marietta, Georgia, United States
      • Shionogi Research Site
  • Louisiana
    • Shreveport, Louisiana, United States
      • Shionogi Research Site
  • Michigan
    • Caro, Michigan, United States
      • Shionogi Research Site
    • Flint, Michigan, United States
      • Shionogi Research Site
  • Missouri
    • Hazelwood, Missouri, United States
      • Shionogi Research Site
  • Nevada
    • Las Vegas, Nevada, United States
      • Shionogi Research Site
  • New Jersey
    • Belvidere, New Jersey, United States
      • Shionogi Research Site
    • East Brunswick, New Jersey, United States
      • Shionogi Research Site
  • New Mexico
    • Albuquerque, New Mexico, United States
      • Shionogi Research Site
  • New York
    • Great Neck, New York, United States
      • Shionogi Research Site
    • Hollis, New York, United States
      • Shionogi Research Site
    • New Windsor, New York, United States
      • Shionogi Research Site
  • North Carolina
    • Winston-Salem, North Carolina, United States
      • Shionogi Research Site
  • Ohio
    • Cincinnati, Ohio, United States
      • Shionogi Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • Shionogi Research Site
  • Oregon
    • Medford, Oregon, United States
      • Shionogi Research Site
  • Pennsylvania
    • West Reading, Pennsylvania, United States
      • Shionogi Research Site
  • Tennessee
    • Chattanooga, Tennessee, United States
      • Shionogi Research Site
  • Texas
    • Arlington, Texas, United States
      • Shionogi Research Site
    • Austin, Texas, United States
      • Shionogi Research Site
    • Dallas, Texas, United States
      • Shionogi Research Site
    • Houston, Texas, United States
      • Shionogi Research Site
    • San Antonio, Texas, United States
      • Shionogi Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects aged 18 to 80 years inclusive at the time of informed consent
2. Subjects must have non-malignant chronic pain treated with opioids and must have opioid-induced constipation (OIC)
3. Subjects must be treated with a stable opioid regimen at a total daily dose on average of ≥ 30 mg equivalents of oral morphine sulfate
4. Subjects must not be currently using laxatives or must be willing to discontinue laxative use at Screening and must be willing to use only the rescue laxatives provided throughout the study duration
5. Subjects must meet opioid-induced constipation criteria based on the Bowel Movement and Constipation Assessment (BMCA) Diary

Exclusion Criteria:

1. Evidence of significant structural abnormalities of the gastrointestinal (GI) tract
2. Evidence of active medical diseases affecting bowel transit
3. History or presence of pelvic disorders that may be a cause of constipation
4. Surgery (except for minor procedures) within 60 days of Screening
5. 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)
6. Subjects who have never taken laxatives for the treatment of OIC
7. History of active treatment for cancer within the last 2 years (except for basal cell or squamous cell carcinoma of the skin that have been successfully resected) or tamoxifen [Nolvadex®] and raloxifene [Evista®] when being used for prevention of breast cancer
8. Current use of any prohibited medication including opioid antagonists, partial agonists or mixed agonists/antagonists

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Naldemedine; Participants received 0.2 mg naldemedine orally once daily for 12 weeks.	Drug: Naldemedine; Naldemedine 0.2 mg tablet taken orally once a day; Other Names: Symproic®; S 297995
PLACEBO_COMPARATOR: Placebo; Participants received matching placebo orally once daily for 12 weeks.	Drug: Placebo; Placebo tablet taken orally once a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With a Spontaneous Bowel Movement (SBM) Response	A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of rescue laxative therapy during the 24 hours prior to the BM. A responder was defined as a participant having 9 or more positive response weeks out of the 12-week Treatment Period and 3 positive response weeks out of last 4 weeks of the 12-week Treatment Period. A positive response week was defined as ≥ 3 SBMs per week and an increase from baseline of ≥ 1 SBM per week for that week. If a participant had less than 4 days of diary entries for a week, that week was treated as a "non-response" week. Any participant with insufficient primary endpoint data (data for less than 9 out of 12 weeks of the Treatment Period or less than 3 out of the last 4 weeks of the 12-week Treatment Period) was treated as a non-responder.	12-week treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week	A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of a rescue laxative therapy during the 24 hours prior to the BM. Baseline was defined as the 14 days in the screening period prior to study drug administration.	Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)
Change From Baseline to Week 1 in the Number of Spontaneous Bowel Movements Per Week	A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of a rescue laxative therapy during the 24 hours prior to the BM. Baseline was defined as the 14 days in the screening period prior to study drug administration.	Baseline and Week 1
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements Per Week	A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. A complete spontaneous bowel movement (CSBM) was defined as an SBM which was accompanied by the feeling of complete evacuation.	Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements With No Straining Per Week	A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. The severity of straining with each bowel movement was assessed on the following scale: 0=no straining, 1=mild straining, 2=moderate straining, 3=severe straining, 4=very severe straining. SBMs without straining were defined as SBMs with a straining score of 0.	Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)

Collaborators and Investigators

• Sponsor: Shionogi

Publications and helpful links

General Publications

• Hale ME, Wild JE, Yamada T, Yokota T, Tack J, Andresen V, Drewes AM. Naldemedine is effective in the treatment of opioid-induced constipation in patients with chronic non-cancer pain who had a poor response to laxatives. Therap Adv Gastroenterol. 2021 Jul 31;14:17562848211032320. doi: 10.1177/17562848211032320. eCollection 2021.
• Camilleri M, Hale M, Morlion B, Tack J, Webster L, Wild J. Naldemedine Improves Patient-Reported Outcomes of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain in the COMPOSE Phase 3 Studies. J Pain Res. 2021 Jul 16;14:2179-2189. doi: 10.2147/JPR.S282738. eCollection 2021.
• Tack J, Camilleri M, Hale M, Morlion B, Nalamachu S, Webster L, Wild J. Establishing Minimal Clinically Important Differences in Quality of Life Measures in Opioid-Induced Constipation. Clin Gastroenterol Hepatol. 2022 Apr;20(4):855-863. doi: 10.1016/j.cgh.2021.05.004. Epub 2021 Aug 5.
• Webster LR, Hale ME, Yamada T, Wild JE. A Renal Impairment Subgroup Analysis of the Safety and Efficacy of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain Receiving Opioid Therapy. J Pain Res. 2020 Mar 24;13:605-612. doi: 10.2147/JPR.S237833. eCollection 2020.
• Wild J, Webster L, Yamada T, Hale M. Safety and Efficacy of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain Receiving Opioid Therapy: A Subgroup Analysis of Patients >/= 65 Years of Age. Drugs Aging. 2020 Apr;37(4):271-279. doi: 10.1007/s40266-020-00753-2.
• Wild J, Yamada T, Arjona Ferreira JC, Hale M. Onset of action of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: results from 2 randomized, placebo-controlled, phase 3 trials. Pain. 2019 Oct;160(10):2358-2364. doi: 10.1097/j.pain.0000000000001629.
• Hale M, Wild J, Reddy J, Yamada T, Arjona Ferreira JC. Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials. Lancet Gastroenterol Hepatol. 2017 Aug;2(8):555-564. doi: 10.1016/S2468-1253(17)30105-X. Epub 2017 May 30.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 29, 2013
• Primary Completion (ACTUAL): January 22, 2015
• Study Completion (ACTUAL): January 22, 2015

Study Registration Dates

• First Submitted: September 30, 2013
• First Submitted That Met QC Criteria: October 15, 2013
• First Posted (ESTIMATE): October 18, 2013

Study Record Updates

• Last Update Posted (ACTUAL): May 30, 2017
• Last Update Submitted That Met QC Criteria: April 19, 2017
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: Opioid-induced Constipation
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Signs and Symptoms, Digestive; Narcotic-Related Disorders; Constipation; Opioid-Induced Constipation
• Other Study ID Numbers: 1314V9231; 2013-002241-11 (EUDRACT_NUMBER)