Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial of Linaclotide Administered to Patients With Opioid-Induced Constipation Receiving Chronic Opioid Treatment for Non-Cancer Pain

A Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial of Linaclotide Administered Orally for 8 Weeks to Adult Outpatients With Opioid-Induced Constipation Receiving Chronic Opioid Treatment for Non-Cancer Pain

The purpose of this study was to evaluate the safety and efficacy of linaclotide for the treatment of opioid-induced constipation (OIC), in adults receiving stable opioid treatment for chronic non-cancer pain that has been present for a minimum of 3 months.

This study included up to a 4-week Screening Period, and a 2 to 3-week Pretreatment Period. Patients meeting the entry criteria were randomized to 1 of 2 doses of linaclotide or placebo once per day for 8 weeks. This 8-week study assessed the effects of linaclotide on bowel movement frequency, as well as other bowel symptoms of OIC.

Study Overview

• Status: Completed
• Conditions: Opioid-Induced Constipation
• Intervention / Treatment: Drug: Placebo; Drug: Linaclotide 145 micrograms; Drug: Linaclotide 290 micrograms

• Study Type: Interventional
• Enrollment (Actual): 254
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Forest Investigative Site 002
    • Foley, Alabama, United States, 36535
      • Forest Investigative Site 001
  • Arizona
    • Phoenix, Arizona, United States, 85029
      • Forest Investigative Site 007
    • Tucson, Arizona, United States, 85710
      • Forest Investigative Site 008
  • Arkansas
    • North Little Rock, Arkansas, United States, 72217
      • Forest Investigative Site 003
  • California
    • Anaheim, California, United States, 92801
      • Forest Investigative Site 018
    • Fountain Valley, California, United States, 92708
      • Forest Investigative Site 014
    • Fresno, California, United States, 93702
      • Forest Investigative Site 019
    • Garden Grove, California, United States, 92843
      • Forest Investigative Site 017
    • Gold River, California, United States, 95670
      • Forest Investigative Site 010
    • Lincoln, California, United States, 95648
      • Forest Investigative Site 009
    • North Hollywood, California, United States, 91606
      • Forest Investigative Site 012
    • Orange, California, United States, 92868
      • Forest Investigative Site 011
    • Sacramento, California, United States, 95821
      • Forest Investigative Site 016
    • San Diego, California, United States, 92108
      • Forest Investigative Site 013
    • Santa Ana, California, United States, 92701
      • Forest Investigative Site 015
  • Colorado
    • Colorado Springs, Colorado, United States, 80904
      • Forest Investigative Site 020
  • Connecticut
    • Bristol, Connecticut, United States, 06010
      • Forest Investigative Site 021
  • Florida
    • Boynton Beach, Florida, United States, 33426
      • Forest Investigative Site 035
    • Bradenton, Florida, United States, 34208
      • Forest Investigative Site 038
    • DeLand, Florida, United States, 32720
      • Forest Investigative Site 024
    • Gainesville, Florida, United States, 32607
      • Forest Investigative Site 027
    • Jacksonville, Florida, United States, 32257
      • Forest Investigative Site 023
    • Jupiter, Florida, United States, 33458
      • Forest Investigative Site 036
    • Lauderdale Lakes, Florida, United States, 33319
      • Forest Investigative Site 037
    • Miami, Florida, United States, 33185
      • Forest Investigative Site 028
    • Orlando, Florida, United States, 32801
      • Forest Investigative Site 040
    • Oviedo, Florida, United States, 32765
      • Forest Investigative Site 022
    • Port Orange, Florida, United States, 32129
      • Forest Investigative Site 034
    • Seminole, Florida, United States, 33777
      • Forest Investigative Site 029
    • Tampa, Florida, United States, 33606
      • Forest Investigative Site 033
    • Tampa, Florida, United States, 33603
      • Forest Investigative Site 031
    • Tampa, Florida, United States, 33613
      • Forest Investigative Site 030
    • West Palm Beach, Florida, United States, 33409
      • Forest Investigative Site 039
    • Weston, Florida, United States, 33331
      • Forest Investigative Site 032
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Forest Investigative Site 041
    • Woodstock, Georgia, United States, 30189
      • Forest Investigative Site 042
  • Illinois
    • Chicago, Illinois, United States, 60616
      • Forest Investigative Site 043
  • Indiana
    • Evansville, Indiana, United States, 47714
      • Forest Investigative Site 044
  • Kentucky
    • Madisonville, Kentucky, United States, 42431
      • Forest Investigative Site 045
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • Forest Investigative Site 046
  • Maryland
    • Hagerstown, Maryland, United States, 21742
      • Forest Investigative Site 048
  • Massachusetts
    • Watertown, Massachusetts, United States, 02472
      • Forest Investigative Site 047
  • Michigan
    • Chesterfield, Michigan, United States, 48047
      • Forest Investigative Site 050
    • Flint, Michigan, United States, 48504
      • Forest Investigative Site 049
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Forest Investigative Site 058
    • Omaha, Nebraska, United States, 68134
      • Forest Investigative Site 057
  • New York
    • Williamsville, New York, United States, 14221
      • Forest Investigative Site 059
  • North Carolina
    • Asheboro, North Carolina, United States, 27203
      • Forest Investigative Site 082
    • Chapel Hill, North Carolina, United States, 27514
      • Forest Investigative Site 054
    • Davidson, North Carolina, United States, 28036
      • Forest Investigative Site 088
    • Flat Rock, North Carolina, United States, 28731
      • Forest Investigative Site 051
    • Greensboro, North Carolina, United States, 27403
      • Forest Investigative Site 052
    • Greensboro, North Carolina, United States, 27410
      • Forest Investigative Site 055
    • Winston-Salem, North Carolina, United States, 27103
      • Forest Investigative Site 053
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Forest Investigative Site 056
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Forest Investigative Site 062
    • Columbus, Ohio, United States, 43213
      • Forest Investigative Site 061
    • Mentor, Ohio, United States, 44060
      • Forest Investigative Site 060
    • Wadsworth, Ohio, United States, 44281
      • Forest Investigative Site 087
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • Forest Investigative Site 064
    • Oklahoma City, Oklahoma, United States, 73120
      • Forest Investigative Site 063
    • Tulsa, Oklahoma, United States, 74104
      • Forest Investigative Site 065
  • Oregon
    • Medford, Oregon, United States, 97504
      • Forest Investigative Site 066
  • Pennsylvania
    • Levittown, Pennsylvania, United States, 19056
      • Forest Investigative Site 067
    • Philadelphia, Pennsylvania, United States, 19140
      • Forest Investigative Site 080
  • Rhode Island
    • Cumberland, Rhode Island, United States, 02864
      • Forest Investigative Site 068
  • South Carolina
    • Charleston, South Carolina, United States, 29406
      • Forest Investigative Site 070
  • Texas
    • Richardson, Texas, United States, 75080
      • Forest Investigative Site 083
    • San Antonio, Texas, United States, 78209
      • Forest Investigative Site 074
    • San Antonio, Texas, United States, 78215
      • Forest Investigative Site 073
    • San Antonio, Texas, United States, 78229
      • Forest Investigative Site 071
  • Utah
    • Logan, Utah, United States, 84341
      • Forest Investigative Site 075
    • Ogden, Utah, United States, 84341
      • Forest Investigative Site 084
    • West Jordan, Utah, United States, 84088
      • Forest Investigative Site 076
  • Virginia
    • Christiansburg, Virginia, United States, 24073
      • Forest Investigative Site 078
  • Washington
    • Bellevue, Washington, United States, 98007
      • Forest Investigative Site 079

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:

• Patient has chronic non-cancer pain that has been present for a minimum of 3 months
• Patient has been receiving a stable oral dose of a full-opioid agonist for at least 4 days per week during the 8 consecutive weeks

• Patient meets protocol criteria for Opioid-Induced Constipation (OIC): < 3 spontaneous bowel movements (SBMs) per week and reports one of the following symptoms for at least 4 weeks:

  1. Straining during > 25% of BMs
  2. Lumpy or hard stools during > 25% of BMs
  3. Sensation of incomplete evacuation during > 25% of BMs
• Patient meets the colonoscopy requirements defined by the American Gastroenterological Association guidelines
• Patient has successfully completed protocol procedures (with no clinically significant findings)
• Patient is compliant with Interactive Voice Response System (IVRS) for daily diary reporting
• Patient has a total of < 6 SBMs in IVRS during the 14 days before and up to the time of Randomization
• Patient has adequate relief and well-controlled pain with current dose of opioid

Exclusion Criteria:

• Patient has been using opioids for abdominal pain
• Patient has symptoms of or been diagnosed with chronic constipation or chronic idiopathic constipation prior to initiation of opioid treatment
• Patient has symptoms of or been diagnosed with Irritable Bowel Syndrome (IBS) prior to initiation of opioid treatment
• Patient has a history of loose or watery stools for > 25% of BMs during the 3 months before the Screening in the absence of laxatives, suppositories, or enemas
• Patient has a structural abnormality of the gastrointestinal (GI) tract or a disease or condition that can affect GI motility
• Patient has any protocol-excluded or clinically significant medical or surgical history that would limit the patient's ability to complete or participate in this clinical trial or could confound the study assessments

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Linaclotide 145 micrograms; Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast.	Drug: Linaclotide 145 micrograms; Other Names: Linzess
Experimental: Linaclotide 290 micrograms; Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast.	Drug: Linaclotide 290 micrograms; Other Names: Linzess
Experimental: Placebo; Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast.	Drug: Placebo; Matching placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 8-Week SBM Frequency Rate (SBMs/Week)	Change from baseline in 8-Week SBM frequency rate (SBMs/week) during the Treatment Period.	Baseline (Week 0) to Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First SBM After the First Dose of Investigational Product	The median time to the first SBM after the first dose of investigational product	Baseline (Day 0) up to 8 weeks
Percentage of Participants Meeting 6/8 Week Spontaneous Bowel Movement (SBM) 3 + 1 Responder Criteria	A 6/8 Week SBM 3 + 1 responder was a participant who met the weekly SBM 3 + 1 responder criteria for at least 6 out of the 8 weeks of the Treatment Period. For each week in the Treatment Period, a weekly SBM 3 + 1 responder was a patient who had an SBM weekly rate ≥ 3 and an increase ≥ 1 in the SBM weekly rate from baseline for that week.	8-week treatment period
Change From Baseline in 8-Week Stool Consistency	Stool Consistency was assessed using the 7-Point Bristol Stool Form Scale: = separate hard lumps like nuts (difficult to pass); = sausage shaped but lumpy; = like a sausage but with cracks on surface; = like a sausage or snake, smooth and soft; = soft blobs with clear-cut edges (passed easily); = fluffy pieces with ragged edges, a mushy; = watery, no solid pieces (entirely liquid)	Baseline (Week 0) to Week 8
Change From Baseline in 8-Week Straining	Straining was measured on a 5-point ordinal scale where a value of 1 is "not at all" and a value of 5 is "an extreme amount."	Baseline (Week 0) to Week 8
Change From Baseline in 8-Week Abdominal Bloating	Abdominal bloating was collected daily via IVRS calls and measured using an 11-point numerical rating scale, where 0 represents no abdominal bloating and 10 represents very severe abdominal bloating.	Baseline (Week 0) to Week 8

Collaborators and Investigators

• Sponsor: Forest Laboratories
• Collaborators: Ironwood Pharmaceuticals, Inc.
• Investigators: Study Director: Patricia D'Astoli, RN, Forest Laboratories, LLC, an Allergan Affiliate

Publications and helpful links

General Publications

• Brenner DM, Argoff CE, Fox SM, Bochenek W, D'Astoli P, Blakesley RE, Reasner DS, O'Dea CR, Cash BD. Efficacy and safety of linaclotide for opioid-induced constipation in patients with chronic noncancer pain syndromes from a phase 2 randomized study. Pain. 2020 May;161(5):1027-1036. doi: 10.1097/j.pain.0000000000001754.

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2014
• Primary Completion (Actual): August 31, 2015
• Study Completion (Actual): October 31, 2015

Study Registration Dates

• First Submitted: October 16, 2014
• First Submitted That Met QC Criteria: October 20, 2014
• First Posted (Estimate): October 22, 2014

Study Record Updates

• Last Update Posted (Actual): April 8, 2019
• Last Update Submitted That Met QC Criteria: April 4, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Opioid-Induced Constipation; Linzess; Linaclotide
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Signs and Symptoms, Digestive; Narcotic-Related Disorders; Constipation; Opioid-Induced Constipation; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Enzyme Activators; Linaclotide
• Other Study ID Numbers: LIN-MD-40