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Efficacy and Safety of Naldemedine in Treating Opioid-induced Constipation

Primary Purpose

Opioid-induced Constipation

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Naldemedine
Placebo
Sponsored by
Shionogi
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Opioid-induced Constipation focused on measuring Opioid-induced Constipation

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Subjects aged 18 to 80 years inclusive at the time of informed consent
  • Subjects must have non-malignant chronic pain treated with opioids 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 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
  • Subjects must meet opioid-induced constipation criteria based on the Bowel Movement and Constipation Assessment (BMCA) Diary

Exclusion Criteria:

  • Evidence of significant structural abnormalities of the gastrointestinal (GI) tract
  • Evidence of active medical diseases affecting bowel transit
  • History or presence 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
  • 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
  • Current use of any prohibited medication including opioid antagonists, partial agonists, or mixed agonists/antagonists

Sites / Locations

  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site
  • Shionogi Research Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Naldemedine

Placebo

Arm Description

Participants received 0.2 mg naldemedine orally once daily for 12 weeks.

Participants received matching placebo orally once daily for 12 weeks.

Outcomes

Primary Outcome Measures

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 the 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

Secondary Outcome Measures

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.
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.
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.
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.

Full Information

First Posted
November 19, 2013
Last Updated
April 19, 2017
Sponsor
Shionogi
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1. Study Identification

Unique Protocol Identification Number
NCT01993940
Brief Title
Efficacy and Safety of Naldemedine in Treating Opioid-induced Constipation
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
November 4, 2013 (Actual)
Primary Completion Date
June 9, 2015 (Actual)
Study Completion Date
June 9, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shionogi

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Opioid-induced Constipation
Keywords
Opioid-induced Constipation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
553 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Naldemedine
Arm Type
Experimental
Arm Description
Participants received 0.2 mg naldemedine orally once daily for 12 weeks.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants received matching placebo orally once daily for 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Naldemedine
Other Intervention Name(s)
S-297995, Symproic®
Intervention Description
Naldemedine 0.2 mg tablet taken orally once a day
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo tablet taken orally once a day
Primary Outcome Measure Information:
Title
Percentage of Participants With a Spontaneous Bowel Movement (SBM) Response
Description
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 the 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
Time Frame
12-week treatment period
Secondary Outcome Measure Information:
Title
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week
Description
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.
Time Frame
Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)
Title
Change From Baseline to Week 1 in the Number of Spontaneous Bowel Movements Per Week
Description
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.
Time Frame
Baseline and Week 1
Title
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements Per Week
Description
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.
Time Frame
Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)
Title
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements With No Straining Per Week
Description
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.
Time Frame
Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects aged 18 to 80 years inclusive at the time of informed consent Subjects must have non-malignant chronic pain treated with opioids 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 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 Subjects must meet opioid-induced constipation criteria based on the Bowel Movement and Constipation Assessment (BMCA) Diary Exclusion Criteria: Evidence of significant structural abnormalities of the gastrointestinal (GI) tract Evidence of active medical diseases affecting bowel transit History or presence 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 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 Current use of any prohibited medication including opioid antagonists, partial agonists, or mixed agonists/antagonists
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Shionogi Clinical Trials Administrator Clinical Support Help Line
Organizational Affiliation
Shionogi
Official's Role
Study Director
Facility Information:
Facility Name
Shionogi Research Site
City
Birmingham
State/Province
Alabama
Country
United States
Facility Name
Shionogi Research Site
City
Homewood
State/Province
Alabama
Country
United States
Facility Name
Shionogi Research Site
City
Goodyear
State/Province
Arizona
Country
United States
Facility Name
Shionogi Research Site
City
Little Rock
State/Province
Arkansas
Country
United States
Facility Name
Shionogi Research Site
City
Anaheim
State/Province
California
Country
United States
Facility Name
Shionogi Research Site
City
Buena Park
State/Province
California
Country
United States
Facility Name
Shionogi Research Site
City
Corona
State/Province
California
Country
United States
Facility Name
Shionogi Research Site
City
Gold River
State/Province
California
Country
United States
Facility Name
Shionogi Research Site
City
Los Angeles
State/Province
California
Country
United States
Facility Name
Shionogi Research Site
City
Modesto
State/Province
California
Country
United States
Facility Name
Shionogi Research Site
City
Pasadena
State/Province
California
Country
United States
Facility Name
Shionogi Research Site
City
Coral Gables
State/Province
Florida
Country
United States
Facility Name
Shionogi Research Site
City
Hialeah
State/Province
Florida
Country
United States
Facility Name
Shionogi Research Site
City
Jacksonville
State/Province
Florida
Country
United States
Facility Name
Shionogi Research Site
City
Miami Beach
State/Province
Florida
Country
United States
Facility Name
Shionogi Research Site
City
Miami
State/Province
Florida
Country
United States
Facility Name
Shionogi Research Site
City
Plantation
State/Province
Florida
Country
United States
Facility Name
Shionogi Research Site
City
Columbus
State/Province
Georgia
Country
United States
Facility Name
Shionogi Research Site
City
Evansville
State/Province
Indiana
Country
United States
Facility Name
Shionogi Research Site
City
Indianapolis
State/Province
Indiana
Country
United States
Facility Name
Shionogi Research Site
City
West Des Moines
State/Province
Iowa
Country
United States
Facility Name
Shionogi Research Site
City
Edgewood
State/Province
Kentucky
Country
United States
Facility Name
Shionogi Research Site
City
Crowley
State/Province
Louisiana
Country
United States
Facility Name
Shionogi Research Site
City
Kalamazoo
State/Province
Michigan
Country
United States
Facility Name
Shionogi Research Site
City
Traverse City
State/Province
Michigan
Country
United States
Facility Name
Shionogi Research Site
City
Butte
State/Province
Montana
Country
United States
Facility Name
Shionogi Research Site
City
Omaha
State/Province
Nebraska
Country
United States
Facility Name
Shionogi Research Site
City
Las Vegas
State/Province
Nevada
Country
United States
Facility Name
Shionogi Research Site
City
Omaha
State/Province
Nevada
Country
United States
Facility Name
Shionogi Research Site
City
Albuquerque
State/Province
New Mexico
Country
United States
Facility Name
Shionogi Research Site
City
Hopewell Junction
State/Province
New York
Country
United States
Facility Name
Shionogi Research Site
City
Mooresville
State/Province
North Carolina
Country
United States
Facility Name
Shionogi Research Site
City
Winston-Salem
State/Province
North Carolina
Country
United States
Facility Name
Shionogi Research Site
City
Dayton
State/Province
Ohio
Country
United States
Facility Name
Shionogi Research Site
City
Marion
State/Province
Ohio
Country
United States
Facility Name
Shionogi Research Site
City
Media
State/Province
Pennsylvania
Country
United States
Facility Name
Shionogi Research Site
City
Spartanburg
State/Province
South Carolina
Country
United States
Facility Name
Shionogi Research Site
City
Knoxville
State/Province
Tennessee
Country
United States
Facility Name
Shionogi Research Site
City
Tullahoma
State/Province
Tennessee
Country
United States
Facility Name
Shionogi Research Site
City
Channelview
State/Province
Texas
Country
United States
Facility Name
Shionogi Research Site
City
Fort Worth
State/Province
Texas
Country
United States
Facility Name
Shionogi Research Site
City
Groesbeck
State/Province
Texas
Country
United States
Facility Name
Shionogi Research Site
City
Houston
State/Province
Texas
Country
United States
Facility Name
Shionogi Research Site
City
Plano
State/Province
Texas
Country
United States
Facility Name
Shionogi Research Site
City
San Antonio
State/Province
Texas
Country
United States
Facility Name
Shionogi Research Site
City
Chesapeake
State/Province
Virginia
Country
United States
Facility Name
Shionogi Research Site
City
Chester
State/Province
Virginia
Country
United States
Facility Name
Shionogi Research Site
City
Tacoma
State/Province
Washington
Country
United States
Facility Name
Shionogi Research Site
City
Clarksburg
State/Province
West Virginia
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
34377150
Citation
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.
Results Reference
derived
PubMed Identifier
34295186
Citation
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.
Results Reference
derived
PubMed Identifier
33965574
Citation
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.
Results Reference
derived
PubMed Identifier
32280263
Citation
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.
Results Reference
derived
PubMed Identifier
32086791
Citation
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.
Results Reference
derived
PubMed Identifier
31145214
Citation
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.
Results Reference
derived
PubMed Identifier
28576452
Citation
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.
Results Reference
derived

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Efficacy and Safety of Naldemedine in Treating Opioid-induced Constipation

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