A Trial of Linaclotide 290 μg in Patients With Irritable Bowel Syndrome With Constipation (IBS-C)

A Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial of Linaclotide 290 μg Administered Orally for 12 Weeks Followed by a 4-week Randomized Withdrawal Period in Patients With Irritable Bowel Syndrome With Constipation

To evaluate the efficacy on abdominal symptoms (abdominal bloating, abdominal discomfort, and abdominal pain) and safety of linaclotide 290 μg administered orally to patients with IBS-C.

Study Overview

• Status: Completed
• Conditions: Irritable Bowel Syndrome Characterized by Constipation
• Intervention / Treatment: Drug: Linaclotide; Drug: Placebo

Detailed Description

This study consists of a 12-week Treatment Period followed by 4-week Randomized Withdrawal (RW) Period.

• Study Type: Interventional
• Enrollment (Actual): 614
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Clinical Research Associates
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • Elite Clinical Studies
    • Tucson, Arizona, United States, 85712
      • Adobe Clinical Research, LLC
  • Arkansas
    • North Little Rock, Arkansas, United States, 72117
      • Arkansas Gastroenterology
  • California
    • Chula Vista, California, United States, 91910
      • GW Research, Inc.
    • Corona, California, United States, 92879
      • Kindred Medical Institute for Clinical Trials, LLC
    • Encinitas, California, United States, 92024
      • Diagnamics, Inc.
    • Fountain Valley, California, United States, 92708
      • MD Studies, Inc.
    • Garden Grove, California, United States, 92840
      • Paragon Rx Clinical, Inc. - Garden Grove
    • La Mesa, California, United States, 91942
      • Grossmont Center for Clinical Research
    • Mission Hills, California, United States, 91345
      • Facey Medical Foundation
    • North Hollywood, California, United States, 91606
      • Providence Clinical Research
    • San Diego, California, United States, 92114
      • Precision Research Institute
    • Santa Ana, California, United States, 92703
      • Paragon Rx Clinical, Inc.- Santa Ana
    • Thousand Oaks, California, United States, 91360
      • Millennium Clinical Trials
    • Yorba Linda, California, United States, 92886
      • St. Joseph Heritage Healthcare
  • Connecticut
    • Bristol, Connecticut, United States, 06010
      • Connecticut Clinical Research Institute
    • Waterbury, Connecticut, United States, 06708
      • Chase Medical Research, LLC
  • Florida
    • Coral Gables, Florida, United States, 33134
      • Clinical Research of South Florida
    • DeLand, Florida, United States, 32720
      • Avail Clinical Research, LLC
    • Hialeah, Florida, United States, 33016
      • Palmetto Research, LLC
    • Inverness, Florida, United States, 34452
      • Nature Coast Clinical Research, LLC
    • Kissimmee, Florida, United States, 34741
      • The Chappel Group Research
    • Miami, Florida, United States, 33175
      • New Horizon Research Center
    • Miami, Florida, United States, 33134
      • Jesscan Medical Research
    • Miami, Florida, United States, 33143
      • Well Pharma Medical Research Corporation
    • Miami Lakes, Florida, United States, 33014
      • San Marcus Research Clinic, Inc.
    • Miami Springs, Florida, United States, 33166
      • Ocean Blue Medical Research Center, Inc.
    • Ormond Beach, Florida, United States, 32174
      • Ormond Medical Arts Pharmaceutical Research Center
    • Sunrise, Florida, United States, 33351
      • Precision Clinical Research
    • Tampa, Florida, United States, 33634
      • Meridien Research - Tampa
    • West Palm Beach, Florida, United States, 33409
      • Palm Beach Research Center
    • Winter Park, Florida, United States, 32792
      • Research Institute of Central Florida, LLC
  • Georgia
    • Sandy Springs, Georgia, United States, 30328
      • Mount Vernon Clinical Research, LLC
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • Clinical Trials Management, LLC
    • Monroe, Louisiana, United States, 71201
      • Delta Research Partners, LLC
    • Shreveport, Louisiana, United States, 71105
      • Louisiana Research Center, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Alan A. Rosen, MD, PA
    • Hagerstown, Maryland, United States, 21742
      • Meritus Center for Clinical Research
  • Massachusetts
    • Boston, Massachusetts, United States, 02131
      • Boston Clinical Trials, Inc.
    • Watertown, Massachusetts, United States, 02472
      • MedVadis Research Corporation
  • Michigan
    • Wyoming, Michigan, United States, 49519
      • Gastroenterology Associates of West Michigan
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Gastrointestinal Associates PA
  • Missouri
    • Saint Louis, Missouri, United States, 63128
      • St. Louis Center for Clinical Research
  • Montana
    • Bozeman, Montana, United States, 59718
      • Bozeman Health Deaconess Hospital
  • Nevada
    • Las Vegas, Nevada, United States, 89121
      • Clinical Research of South Nevada
  • New York
    • Brooklyn, New York, United States, 11206
      • Healthwise Medical Associates
    • Great Neck, New York, United States, 11023
      • Long Island Gastrointestinal Research Group, LLP
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Carolina Digestive Health Associates
    • Concord, North Carolina, United States, 28025
      • Carolina Digestive Health Associates
    • Fayetteville, North Carolina, United States, 28304
      • Cumberland Research Associates
    • High Point, North Carolina, United States, 27262
      • Peters Medical Research, LLC
    • Raleigh, North Carolina, United States, 27612
      • Wake Research Associates, LLC
    • Wilmington, North Carolina, United States, 28401
      • PMG Research of Wilmington
    • Winston-Salem, North Carolina, United States, 27103
      • Lyndhurst Clinical Research
    • Winston-Salem, North Carolina, United States, 27103
      • Clinical Trials of America - North Carolina, LLC
    • Winston-Salem, North Carolina, United States, 27103
      • PMG Research of Winston-Salem
  • North Dakota
    • Fargo, North Dakota, United States, 58104
      • Lillestol Research
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • New Horizons Clinical Research
    • Cincinnati, Ohio, United States, 45224
      • Hightop Medical Research Center
    • Columbus, Ohio, United States, 43215
      • Remington Davis, Inc.
    • Dayton, Ohio, United States, 45424
      • Hometown Urgent Care and Research
    • Dayton, Ohio, United States, 45415
      • Dayton Gastroenterology, Inc.
    • Mentor, Ohio, United States, 44060
      • Great Lakes Gastroenterology Research, LLC
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73106
      • IPS Research Company
  • Rhode Island
    • Cumberland, Rhode Island, United States, 02864
      • Partners in Clinical Research
  • South Carolina
    • Greer, South Carolina, United States, 29651
      • Mountain View Clinical Research, Inc.
  • South Dakota
    • Dakota Dunes, South Dakota, United States, 57049
      • Meridian Clinical Research
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • ClinSearch, LLC
    • Knoxville, Tennessee, United States, 37909
      • New Phase Research & Development
  • Texas
    • Beaumont, Texas, United States, 77701
      • MW Clinical Research Center
    • Houston, Texas, United States, 77074
      • Southwest Clinical Trials
    • Houston, Texas, United States, 77081
      • Southwest Clinical Trials
    • San Antonio, Texas, United States, 78229
      • Diagnostics Research Group
    • San Antonio, Texas, United States, 78209
      • Quality Research, Inc.
    • San Antonio, Texas, United States, 78258
      • Stone Oak, LLC dba Discovery Clinical Trials
  • Utah
    • Ogden, Utah, United States, 84405
      • Advanced Research Institute
  • Virginia
    • Christiansburg, Virginia, United States, 24073
      • New River Valley Research Institute
    • Lynchburg, Virginia, United States, 24502
      • Blue Ridge Medical Research

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 no clinically significant findings on a physical examination and clinical laboratory tests

• Female patients of childbearing potential must agree to use one of the following methods of birth control:

  1. Hormonal contraception
  2. Double-barrier birth control
  3. Maintenance of a monogamous relationship with a male partner who has been surgically sterilized by vasectomy
• Patient meets protocol criteria for diagnosis of IBS-C
• Patient demonstrates continued IBS-C symptoms through Pretreatment Period
• Patient maintains a minimum level of compliance with daily diary

Exclusion Criteria:

• Patient has history of loose or watery stools
• Patient has symptoms of or been diagnosed with a medical condition that may contribute to abdominal pain
• 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 could confound the study assessments

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Linaclotide 290 µg; Participants receive linaclotide 290 µg orally once daily for 12 weeks during the Treatment Period. At Week 12 participants are rerandomized to receive either linaclotide 290 µg or placebo for 4 weeks in the Randomized Withdrawal Period.	Drug: Linaclotide; Oral capsule; Other Names: Linzess; Drug: Placebo; Matching placebo oral capsule
Placebo Comparator: Placebo; Participants receive placebo to linaclotide orally once daily for 12 weeks during the Treatment Period. At Week 12 participants are switched to receive linaclotide 290 µg for 4 weeks during the Randomized Withdrawal Period.	Drug: Linaclotide; Oral capsule; Other Names: Linzess; Drug: Placebo; Matching placebo oral capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Throughout the Treatment Period	A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was derived from the eDiary data collected daily in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization. The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period and used as the dependent variable in the mixed model with repeated measures (MMRM) model. MMRM results are based on a model with treatment, analysis week, region and treatment-by-week interaction as fixed effects and baseline as a covariate. An unstructured covariance structure was used to model intra-subject correlation with subjects as a random effect.	Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Distribution of Change From Baseline in 12-Week Abdominal Score	A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was derived from the eDiary data collected daily in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization. The 12-week abdominal score was the average of the non-missing abdominal scores reported over the course of the treatment period. Change from baseline (BL) was calculated as the 12-week score minus the baseline score. The table presents the percentage of participants whose 12-week change from baseline was less than or equal to the threshold value of the score change (cumulative distribution of change).	Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)
Percentage of 6/12 Week Abdominal Score Responders (Responder Rate)	A 6/12 week abdominal score responder is a participant who meets the weekly abdominal score responder criteria for at least 6 out of the 12 weeks of the Treatment Period. For each week in the Treatment Period, a weekly abdominal score responder is a participant who has an improvement from baseline of at least 2 points (ie, a -2 point change from baseline) in the respective weekly abdominal score. If a participant did not have at least 4 completed eDiary entries for a particular Treatment Period week, the participant was not considered a responder for that week. A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period.	Baseline (14 days before randomization up to the time of randomization), Treatment Period (Weeks 1-12)
Overall Change From Baseline in Abdominal Score (Abdominal Bloating, Abdominal Discomfort, and Abdominal Pain) Over Time in the Treatment Period	A participant's daily abdominal score was calculated as the average of daily e-diary abdominal pain, abdominal bloating and abdominal discomfort scores, each based on an 11-point scale of 0 (none) and 10 (worst possible). Baseline abdominal score was derived from the eDiary data collected daily in the Pretreatment Period, specifically the period of time from 14 days before randomization up to the time of randomization. The participant's abdominal score was averaged on a weekly basis, and each weekly change from baseline was calculated for the treatment period and used as the dependent variable in the mixed model with repeated measures (MMRM) model. MMRM results are based on a model with treatment, analysis week, region and treatment-by-week interaction as fixed effects and baseline as a covariate. An unstructured covariance structure was used to model intra-subject correlation with subjects as a random effect.	Baseline (14 days before randomization up to the time of randomization), Weeks 1-12

Collaborators and Investigators

• Sponsor: Ironwood Pharmaceuticals, Inc.
• Collaborators: Allergan Sales, LLC

Publications and helpful links

General Publications

• Brenner DM, Lacy BE, Ford AC, Bartolini W, Wu J, Shea EP, Bochenek W, Boinpally R, Almansa C. Linaclotide Reduced Response Time for Irritable Bowel Syndrome With Constipation Symptoms: Analysis of 4 Randomized Controlled Trials. Am J Gastroenterol. 2022 Nov 16. doi: 10.14309/ajg.0000000000002064. [Epub ahead of print]
• Chang L, Lacy BE, Moshiree B, Kassebaum A, Abel JL, Hanlon J, Bartolini W, Boinpally R, Bochenek W, Fox SM, Mallick M, Tripp K, Omniewski N, Shea E, Borgstein N. Efficacy of Linaclotide in Reducing Abdominal Symptoms of Bloating, Discomfort, and Pain: A Phase 3B Trial Using a Novel Abdominal Scoring System. Am J Gastroenterol. 2021 Sep 1;116(9):1929-1937. doi: 10.14309/ajg.0000000000001334.

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2018
• Primary Completion (Actual): March 13, 2019
• Study Completion (Actual): April 10, 2019

Study Registration Dates

• First Submitted: June 18, 2018
• First Submitted That Met QC Criteria: June 27, 2018
• First Posted (Actual): June 29, 2018

Study Record Updates

• Last Update Posted (Actual): December 1, 2020
• Last Update Submitted That Met QC Criteria: November 13, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease; Signs and Symptoms, Digestive; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Syndrome; Irritable Bowel Syndrome; Constipation; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Enzyme Activators; Linaclotide
• Other Study ID Numbers: MCP-103-312

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No