Trial of Linaclotide in Patients With Chronic Idiopathic Constipation

A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial of Linaclotide (72 ug or 145 ug) Administered Orally for 12 Weeks to Patients With Chronic Idiopathic Constipation

The objective of this trial was to determine the efficacy and safety of linaclotide 72 ug administered once daily to patients with chronic idiopathic constipation (CIC). The primary efficacy parameter is the percentage of participants in each dosing group that meet the protocol definition for complete spontaneous bowel movement (CSBM) Overall Responder.

Study Overview

• Status: Completed
• Conditions: Chronic Idiopathic Constipation
• Intervention / Treatment: Drug: Linaclotide; Drug: Matching Placebo

Detailed Description

The trial also included a 145 ug linaclotide treatment arm (an FDA-approved dose for CIC) as an established positive control to validate the study design.

• Study Type: Interventional
• Enrollment (Actual): 1223
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Ironwood Investigational Site
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • Ironwood Investigational Site
    • Tucson, Arizona, United States, 85712
      • Ironwood Investigational Site
  • Arkansas
    • North Little Rock, Arkansas, United States, 72117
      • Ironwood Investigational Site
  • California
    • Anaheim, California, United States, 92801
      • Ironwood Investigational Site
    • Chula Vista, California, United States, 91910
      • Ironwood Investigational Site
    • Garden Grove, California, United States, 92843
      • Ironwood Investigational Site
    • La Mesa, California, United States, 91942
      • Ironwood Investigational Site
    • North Hollywood, California, United States, 91606
      • Ironwood Investigational Site
    • Orange, California, United States, 92868
      • Ironwood Investigational Site
    • San Diego, California, United States, 92108
      • Ironwood Investigational Site
    • Thousand Oaks, California, United States, 91360
      • Ironwood Investigational Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80904
      • Ironwood Investigational Site
  • Connecticut
    • Bristol, Connecticut, United States, 06010
      • Ironwood Investigational Site
  • Florida
    • Boynton Beach, Florida, United States, 33426
      • Ironwood Investigational Site
    • Coral Gables, Florida, United States, 33134
      • Ironwood Investigational Site
    • DeLand, Florida, United States, 32720
      • Ironwood Investigational Site
    • Hialeah, Florida, United States, 33016
      • Ironwood Investigational Site
    • Inverness, Florida, United States, 34452
      • Ironwood Investigational Site
    • Jupiter, Florida, United States, 33458
      • Ironwood Investigational Site
    • Kissimmee, Florida, United States, 34741
      • Ironwood Investigational Site
    • Lauderdale Lakes, Florida, United States, 33319
      • Ironwood Investigational Site
    • Miami, Florida, United States, 33015
      • Ironwood Investigational Site
    • Miami, Florida, United States, 33126
      • Ironwood Investigational Site
    • Miami, Florida, United States, 33133
      • Ironwood Investigational Site
    • Miami, Florida, United States, 33135
      • Ironwood Investigational Site
    • Miami, Florida, United States, 33165
      • Ironwood Investigational Site
    • Miami, Florida, United States, 33175
      • Ironwood Investigational Site
    • Orlando, Florida, United States, 32806
      • Ironwood Investigational Site
    • Ormond Beach, Florida, United States, 32174
      • Ironwood Investigational Site
    • Port Orange County, Florida, United States, 32129
      • Ironwood Investigational Site
    • South Miami, Florida, United States, 33143
      • Ironwood Investigational Site
    • Tampa, Florida, United States, 33634
      • Ironwood Investigational Site
    • West Palm Beach, Florida, United States, 33409
      • Ironwood Investigational Site
    • Winter Park, Florida, United States, 32792
      • Ironwood Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • Ironwood Investigational Site
    • Oakwood, Georgia, United States, 30566
      • Ironwood Investigational Site
    • Sandy Springs, Georgia, United States, 30328
      • Ironwood Investigational Site
  • Indiana
    • Evansville, Indiana, United States, 47714
      • Ironwood Investigational Site
  • Louisiana
    • Bastrop, Louisiana, United States, 71220
      • Ironwood Investigational Site
    • Metairie, Louisiana, United States, 70006
      • Ironwood Investigational Site
    • Shreveport, Louisiana, United States, 71103
      • Ironwood Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Ironwood Investigational Site
    • Chevy Chase, Maryland, United States, 20815
      • Ironwood Investigational Site
    • Hagerstown, Maryland, United States, 21740
      • Ironwood Investigational Site
    • Hollywood, Maryland, United States, 20636
      • Ironwood Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02135
      • Ironwood Investigational Site
    • Wellesley, Massachusetts, United States, 02481
      • Ironwood Investigational Site
  • Michigan
    • Chesterfield, Michigan, United States, 48047
      • Ironwood Investigational Site
    • Troy, Michigan, United States, 48098
      • Ironwood Investigational Site
    • Wyoming, Michigan, United States, 49519
      • Ironwood Investigational Site
  • Mississippi
    • Jackson, Mississippi, United States, 39202
      • Ironwood Investigational Site
  • Missouri
    • Saint Louis, Missouri, United States, 63128
      • Ironwood Investigational Site
  • Montana
    • Bozeman, Montana, United States, 59718
      • Ironwood Investigational Site
  • Nevada
    • Las Vegas, Nevada, United States, 89119
      • Ironwood Investigational Site
    • Las Vegas, Nevada, United States, 89121
      • Ironwood Investigational Site
  • New York
    • Brooklyn, New York, United States, 11206
      • Ironwood Investigational Site
    • Endwell, New York, United States, 13760
      • Ironwood Investigational Site
    • Great Neck, New York, United States, 11023
      • Ironwood Investigational Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28209
      • Ironwood Investigational Site
    • Charlotte, North Carolina, United States, 28226
      • Ironwood Investigational Site
    • Greensboro, North Carolina, United States, 27403
      • Ironwood Investigational Site
    • High Point, North Carolina, United States, 27262
      • Ironwood Investigational Site
    • Lenoir, North Carolina, United States, 28645
      • Ironwood Investigational Site
    • Raleigh, North Carolina, United States, 27612
      • Ironwood Investigational Site
    • Wilmington, North Carolina, United States, 28401
      • Ironwood Investigational Site
    • Winston-Salem, North Carolina, United States, 27103
      • Ironwood Investigational Site
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Ironwood Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45224
      • Ironwood Investigational Site
    • Cincinnati, Ohio, United States, 45219
      • Ironwood Investigational Site
    • Columbus, Ohio, United States, 43214
      • Ironwood Investigational Site
    • Mentor, Ohio, United States, 44060
      • Ironwood Investigational Site
    • Sylvania, Ohio, United States, 43560
      • Ironwood Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Ironwood Investigational Site
  • Pennsylvania
    • Levittown, Pennsylvania, United States, 19056
      • Ironwood Investigational Site
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • Ironwood Investigational Site
    • Greer, South Carolina, United States, 29651
      • Ironwood Investigational Site
    • Simpsonville, South Carolina, United States, 29681
      • Ironwood Investigational Site
  • South Dakota
    • Dakota Dunes, South Dakota, United States, 57049
      • Ironwood Investigational Site
  • Tennessee
    • Bristol, Tennessee, United States, 37620
      • Ironwood Investigational Site
    • Chattanooga, Tennessee, United States, 37421
      • Ironwood Investigational Site
    • Knoxville, Tennessee, United States, 37919
      • Ironwood Investigational Site
  • Texas
    • Beaumont, Texas, United States, 77701
      • Ironwood Investigational Site
    • Dallas, Texas, United States, 75230
      • Ironwood Investigational Site
    • El Paso, Texas, United States, 79905
      • Ironwood Investigational Site
    • Houston, Texas, United States, 77074
      • Ironwood Investigational Site
    • Houston, Texas, United States, 77098
      • Ironwood Investigational Site
    • Longview, Texas, United States, 75605
      • Ironwood Investigational Site
    • San Antonio, Texas, United States, 78229
      • Ironwood Investigational Site
    • San Antonio, Texas, United States, 78209
      • Ironwood Investigational Site
    • San Antonio, Texas, United States, 78258
      • Ironwood Investigational Site
  • Utah
    • South Ogden, Utah, United States, 84405
      • Ironwood Investigational Site
  • Virginia
    • Christiansburg, Virginia, United States, 24073
      • Ironwood Investigational Site
    • Lynchburg, Virginia, United States, 24502
      • Ironwood Investigational Site
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Ironwood Investigational 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:

• Patient has completed a colonoscopy if one is needed according to the American Gastroenterological Association (AGA) criteria, with no clinically significant findings
• Patient has no clinically significant findings on a physical examination and clinical laboratory tests
• Patient meets protocol criteria for CIC: reports < 3 bowel movements (BMs) per week and reports one or more of the following during ≥ 25% of BMs: straining, lumpy or hard stools, sensation of incomplete evacuation during the 3 months before the diagnosis with the onset at least 6 months before the diagnosis
• Patient is compliant with daily interactive voice response system (IVRS) calls
• Patient reports an average of < 3 complete spontaneous BMs (CSBMs) and ≤ 6 SBMs per week by the IVRS over the 14 calendar days before the Randomization Visit and the calendar day of Randomization.

Exclusion Criteria:

• Patient has history of loose or watery stools
• Patient has symptoms of or been diagnosed with irritable bowel syndrome (IBS)
• 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
• Patient has Bristol Stool Form Scale score of 7 during Pretreatment period.

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: 72 μg linaclotide; 72 μg oral linaclotide, once daily for 12 weeks	Drug: Linaclotide; Other Names: Linzess; Constella
Experimental: 145 μg linaclotide; 145 μg oral linaclotide, once daily for 12 weeks	Drug: Linaclotide; Other Names: Linzess; Constella
Placebo Comparator: Placebo; matching placebo, once daily for 12 weeks	Drug: Matching Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of 12-Week CSBM Overall Responders	A 12-week CSBM Overall Responder is a participant who was a CSBM Weekly Responder for at least 9 of the 12 weeks of the Treatment Period. A CSBM Weekly Responder is a participant who had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline, and completed ≥ 4 IVRS calls for the specified week. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a bowel movement BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM.	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 12-Week CSBM Frequency Rate	A participant's 12-week CSBM Frequency Rate is the CSBM rate (CSBMs/week) calculated over the 12 weeks of the Treatment Period. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM.	Baseline, Week 1 to Week 12
Change From Baseline in 12-Week SBM Frequency Rate	A participant's 12-week SBM Frequency Rate is the SBM rate (SBMs/week) calculated over the 12-weeks of the Treatment Period. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM.	Baseline, Week 1 to Week 12
Change From Baseline in 12-Week Stool Consistency Score	Stool consistency was measured daily using the 7-point ordinal Bristol Stool Form Scale (BSFS; 1 = separate hard lumps like nuts [difficult to pass]; 2 = sausage shaped but lumpy; 3 = like a sausage but with cracks on surface; 4 = like a sausage or snake, smooth and soft; 5 = soft blobs with clear-cut edges [passed easily]; 6 = fluffy pieces with ragged edges, a mushy stool; 7 = watery, no solid pieces [entirely liquid]). The participant's BSFS score for the Treatment Period is the average of the non-missing BSFS scores from the SBMs reported by the participant during the 12-week Treatment Period.	Baseline, Week 1 to Week 12
Change From Baseline in 12-Week Straining Score	Straining was measured daily using a 5-point ordinal scale (1 = not at all; 2 = a little bit; 3 = a moderate amount; 4 = a great deal; 5 = an extreme amount). The participant's straining score for the Treatment Period is the average of the non-missing straining scores from the SBMs reported by the participant during the 12-week Treatment Period.	Baseline, Week 1 to Week 12
Percentage of 12-Week CSBM Overall Responders (>1 SBM/Week Subpopulation)	A 12-week CSBM Overall Responder is a participant who was a CSBM Weekly Responder for at least 9 of the 12 weeks of the Treatment Period. A CSBM Weekly Responder is a participant who had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline, and completed ≥4 IVRS calls for the specified week. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM.	Week 12
Percentage of Month 1 CSBM Responders	A Month 1 CSBM Responder is a participant who is a CSBM weekly responder for at least 3 of the 4 weeks of Month 1 of the Treatment Period. A CSBM weekly responder is a participant who had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline based on a minimum of 4 complete IVRS calls for that week. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM.	Month 1
Percentage of Month 2 CSBM Responders	A Month 2 CSBM Responder is a participant who is a CSBM weekly responder for at least 3 of the 4 weeks of Month 2 of the Treatment Period. A CSBM weekly responder is a participant who had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline based on a minimum of 4 complete IVRS calls for that week. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM.	Month 2
Percentage of Month 3 CSBM Responders	A Month 3 CSBM Responder is a participant who is a CSBM weekly responder for at least 3 of the 4 weeks of Month 3 of the Treatment Period. A CSBM weekly responder is a participant who had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline based on a minimum of 4 complete IVRS calls for that week. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM.	Month 3
Change From Baseline in 12-Week Abdominal Bloating	Abdominal bloating was measured daily using an 11-point NRS (0 = none; 10 = very severe). The participant's abdominal bloating score for the Treatment Period is the average of the non-missing daily participant assessments of abdominal bloating scores reported during the 12-week Treatment Period.	Baseline, Week 1 to Week 12
Change From Baseline in 12-Week Abdominal Discomfort	Abdominal discomfort was measured daily using an 11-point NRS (0 = none; 10 = very severe). The participant's abdominal discomfort score for the Treatment Period is the average of the non-missing daily participant assessments of abdominal discomfort scores reported during the 12-week Treatment Period.	Baseline, Week 1 to Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of 12-Week CSBM Overall Sustained Responders	A 12-week CSBM Overall Sustained Responder is a participant who was a CSBM Weekly Responder for at least 9 of the 12 weeks of the Treatment Period, including ≥ 3 of the last 4 weeks. A CSBM Weekly Responder is a participant who had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline, and completed ≥ 4 IVRS calls for the specified week. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. An SBM is defined as a BM that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM.	Week 12

Collaborators and Investigators

• Sponsor: Ironwood Pharmaceuticals, Inc.
• Collaborators: Forest Laboratories
• Investigators: Study Chair: Bernard J Lavins, MD, Ironwood Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: November 11, 2014
• First Submitted That Met QC Criteria: November 11, 2014
• First Posted (Estimate): November 14, 2014

Study Record Updates

• Last Update Posted (Actual): June 15, 2017
• Last Update Submitted That Met QC Criteria: May 22, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Constipation; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Enzyme Activators; Linaclotide
• Other Study ID Numbers: MCP-103-309

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No