Phase III, Randomized, Double-Blind, Placebo-Controlled, Trial of Linaclotide Administered to Patients With Chronic Constipation

A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial of Linaclotide Administered Orally for 12 Weeks in Patients With Chronic Constipation

The objective of this trial is to determine the efficacy and safety of linaclotide administered to patients with chronic constipation (CC). The primary efficacy parameter is the percentage of patients in each treatment group that meet the protocol definition for Complete Spontaneous Bowel Movement (CSBM) Overall Responder

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 633
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V67 2K5
      • Forest Investigative Site
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • Forest Investigative Site
    • Newmarket, Ontario, Canada, L3Y 7V1
      • Forest Investigative Site
    • Ottawa, Ontario, Canada, K2c 3R2
      • Forest Investigative Site
    • Sarnia, Ontario, Canada, N7T 4X3
      • Forest Investigative Site 1
    • Sarnia, Ontario, Canada, N7T 4X3
      • Forest Investigative Site 2
    • Sudbury, Ontario, Canada, P3E 1H5
      • Forest Investigative Site
    • Toronto, Ontario, Canada, MCN 2V7
      • Forest Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • Forest Investigative Site
    • Birmingham, Alabama, United States, 35215
      • Forest Investigative Site
    • Huntsville, Alabama, United States, 35801
      • Forest Investigative Site
  • Arizona
    • Chandler, Arizona, United States, 85225
      • Forest Investigative Site
    • Mesa, Arizona, United States, 85210
      • Forest Investigative Site
    • Peoria, Arizona, United States, 85381
      • Forest Investigative Site
    • Phoenix, Arizona, United States, 85012
      • Forest Investigative Site
    • Scottsdale, Arizona, United States, 85251
      • Forest Investigative Site
    • Tucson, Arizona, United States, 85741
      • Forest Investigative Site
  • California
    • Burbank, California, United States, 91505
      • Forest Investigative Site
    • Encinitas, California, United States, 92024
      • Forest Investigative Site
    • Foothill Ranch, California, United States, 92610
      • Forest Investigative Site
    • Los Angeles, California, United States, 90036
      • Forest Investigative Site
    • Orange, California, United States, 92869
      • Forest Investigative Site
    • Westlake Village, California, United States, 91361
      • Forest Investigative Site
  • Colorado
    • Boulder, Colorado, United States, 80304
      • Forest Investigative Site
    • Colorado Springs, Colorado, United States, 80909
      • Forest Investigative Site
    • Denver, Colorado, United States, 80205
      • Forest Investigative Sites
    • Longmont, Colorado, United States, 80501
      • Forest Investigative Site
    • Wheat Ridge, Colorado, United States, 80033
      • Forest Investigative Site
  • Connecticut
    • Waterbury, Connecticut, United States, 06708
      • Forest Investigative Site
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Forest Investigative Site
    • Bradenton, Florida, United States, 34203
      • Forest Investigative Site
    • Brooksville, Florida, United States, 34601
      • Forest Investigative Site
    • Ft. Myers, Florida, United States, 33916
      • Forest Investigative Site
    • Jupiter, Florida, United States, 33458
      • Forest Investigative Site
    • Kissimmee, Florida, United States, 34741
      • Forest Investigative Site
    • Miami, Florida, United States, 33143
      • Forest Investigative Site
    • Ocala, Florida, United States, 34471
      • Forest Investigative Site
    • Orlando, Florida, United States, 32806
      • Forest Investigative Site
    • Panama City, Florida, United States, 32405
      • Forest Investigative Site
    • Pembroke Pines, Florida, United States, 33024
      • Forest Investigative Site
    • St. Petersburg, Florida, United States, 33709
      • Forest Investigative Site
    • Tampa, Florida, United States, 33606
      • Forest Investigative Site
    • Trinity, Florida, United States, 34655
      • Forest Investigative Site
    • Zephyrhills, Florida, United States, 33542
      • Forest Investigative Site
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Forest Investigative Site
    • Marietta, Georgia, United States, 30060
      • Forest Investigative Site
    • Marietta, Georgia, United States, 30067
      • Forest Investigative Site
    • Stockbridge, Georgia, United States, 30281
      • Forest Investigative Site
    • Woodstock, Georgia, United States, 30189
      • Forest Investigative Site
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Forest Investigative Site
  • Illinois
    • Rockford, Illinois, United States, 61107
      • Forest Investigative Site
  • Indiana
    • Elkhart, Indiana, United States, 46514
      • Forest Investigative Site
    • Evansville, Indiana, United States, 47714
      • Forest Investigative Site
    • Indianapolis, Indiana, United States, 46237
      • Forest Investigative Site
    • Indianapolis, Indiana, United States, 46254
      • Forest Investigative Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Forest Investigative Site
  • Kansas
    • Arkansas City, Kansas, United States, 67005
      • Forest Investigative Site
    • Newton, Kansas, United States, 67114
      • Forest Investigative Site
    • Wichita, Kansas, United States, 67205
      • Forest Investigative Site
    • Wichita, Kansas, United States, 67207
      • Forest Investigative Site
  • Kentucky
    • Lexington, Kentucky, United States, 40509
      • Forest Investigative Site
    • Madisonville, Kentucky, United States, 42431
      • Forest Investigative Site
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Forest Investigative Site
    • Hagerstown, Maryland, United States, 21742
      • Forest Investigative Site
    • Lutherville, Maryland, United States, 21093
      • Forest Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02135
      • Forest Investigative Site
  • Minnesota
    • Chaska, Minnesota, United States, 55318
      • Forest Investigative Site
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Forest Investigative Site
    • St. Louis, Missouri, United States, 63128
      • Forest Investigative Site
  • New Jersey
    • Vineland, New Jersey, United States, 08360
      • Forest Investigative Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • Forest Investigative Site
  • New York
    • Brooklyn, New York, United States, 11214
      • Forest Investigative Site
    • Great Neck, New York, United States, 11021
      • Forest Investigative Site
    • Great Neck, New York, United States, 11023
      • Forest Investigative Site
  • North Carolina
    • Fayetteville, North Carolina, United States, 28304
      • Forest Investigative Site
    • Greensboro, North Carolina, United States, 27403
      • Forest Investigative Site
    • Hickory, North Carolina, United States, 28601
      • Forest Investigative Site
    • Raleigh, North Carolina, United States, 27612
      • Forest Investigative Site
    • Wilmington, North Carolina, United States, 28401
      • Forest Investigative Site
    • Winston-Salem, North Carolina, United States, 27103
      • Forest Investigative Site
  • North Dakota
    • Bismark, North Dakota, United States, 58501
      • Forest Investigative Site
  • Ohio
    • Akron, Ohio, United States, 44302
      • Forest Investigative Site
    • Cincinnati, Ohio, United States, 45219
      • Forest Investigative Site
    • Cleveland, Ohio, United States, 44122
      • Forest Investigative Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Forest Investigative Site
    • Tulsa, Oklahoma, United States, 74135
      • Forest Investigative Site
  • Pennsylvania
    • Bensalem, Pennsylvania, United States, 19020
      • Forest Investigative Site
    • Pittsburgh, Pennsylvania, United States, 15206
      • Forest Investigative Site
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Forest Investigative Site
    • Greer, South Carolina, United States, 29651
      • Forest Investigative Site
  • Tennessee
    • Nashville, Tennessee, United States, 37205
      • Forest Investigative Site
  • Texas
    • Austin, Texas, United States, 78705
      • Forest Investigative Site
    • Dallas, Texas, United States, 75234
      • Forest Investigative Site
    • Houston, Texas, United States, 77090
      • Forest Investigative Site
    • Lake Jackson, Texas, United States, 77566
      • Forest Investigative Site
    • San Antonio, Texas, United States, 78229
      • Forest Investigative Site
    • San Antonio, Texas, United States, 78209
      • Forest Investigative Site
  • Utah
    • Salt Lake City, Utah, United States, 84102
      • Forest Investigative Site
  • Virginia
    • Charlottesville, Virginia, United States, 22911
      • Forest Investigative Site
    • Christianburg, Virginia, United States, 24073
      • Forest Investigative Site
    • Newport News, Virginia, United States, 23606
      • Forest Investigative Site
    • Norfolk, Virginia, United States, 23502
      • Forest Investigative Site
    • Norfolk, Virginia, United States, 23507
      • Forest Investigative Site
    • Richmond, Virginia, United States, 23294
      • Forest Investigative Site
  • Washington
    • Bellevue, Washington, United States, 98402
      • Forest Investigative Site
    • Lakewood, Washington, United States, 98499
      • Forest Investigative Site
    • Wenatchee, Washington, United States, 98801
      • Forest Investigative Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53209
      • Forest Investigative 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 according to the AGA criteria, with no clinically significant findings
• Patient has successfully completed protocol procedures (with no clinically significant findings): physical exam, 12-lead ECG, or clinical laboratory tests
• Patient meets protocol criteria for CC: reports < 3 bowel movements per week and reports straining, lumpy or hard stools, and/or sensation of incomplete evacuation during > 25% of BMs
• Patient demonstrates continued chronic constipation through Pretreatment Period
• Patient is compliant with IVRS

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

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: 1; Linaclotide 290 micrograms	Drug: Linaclotide 290 micrograms; Oral, once daily each morning at least 30 minutes before breakfast for the duration of the study
Experimental: 2; Linaclotide 145 micrograms	Drug: Linaclotide 145 micrograms; Oral, once daily each morning at least 30 minutes before breakfast for the duration of the study
Placebo Comparator: 3; Matching placebo	Drug: Placebo; Oral, once daily each morning at least 30 minutes before breakfast for the duration of the study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Spontaneous Bowel Movement (CSBM) Overall Responder	A 12-week CSBM overall responders was defined as a patient who for at least 9 of the 12 weeks of the treatment period had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline. A CSBM was defined as a spontaneous bowel movement (SBM) that was associated with a sense of complete evacuation. An SBM was 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.	Change from Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
12-week Complete Spontaneous Bowel Movement (CSBM) Frequency Rate	The number of CSBMs per week.	Change from Baseline to Week 12
12-Week Spontaneous Bowel Movement (SBM) Frequency Rate	A patient's 12-week spontaneous bowel movement (SBM) frequency rate was the number of SBMs per week calculated over the 12-weeks of the treatment period.	Change from Baseline to Week 12
12-Week Stool Consistency	The consistency of each BM 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 stool; = watery, no solid pieces [entirely liquid]	Change from Baseline to Week 12
12-Week Severity of Straining	Straining is measured on a 5-point scale, where a value of 1 is "not at all" and a value of 5 is "an extreme amount.	Change from Baseline to Week 12
12-Week Abdominal Discomfort	Abdominal discomfort is based on a 5-point scale where a value of l is "none" and a value of 5 is "very severe."	Change from Baseline to Week 12
12-Week Bloating	Bloating was based on a 5-point scale where a value of l is "none" and a value of 5 is "very severe".	Change from Baseline to Week 12
12-Week Constipation Severity	Constipation severity was based on a 5-point ordinal scale where a value of l is "none" and a value of 5 is "very severe".	Change from Baseline to Week 12

Collaborators and Investigators

• Sponsor: Forest Laboratories
• Collaborators: Ironwood Pharmaceuticals, Inc.
• Investigators: Study Director: Paul F.C. Eng, PhD, Forest Laboratories

Publications and helpful links

General Publications

• Chang L, Lembo AJ, Lavins BJ, Shiff SJ, Hao X, Chickering JG, Jia XD, Currie MG, Kurtz CB, Johnston JM. The impact of abdominal pain on global measures in patients with chronic idiopathic constipation, before and after treatment with linaclotide: a pooled analysis of two randomised, double-blind, placebo-controlled, phase 3 trials. Aliment Pharmacol Ther. 2014 Dec;40(11-12):1302-12. doi: 10.1111/apt.12985. Epub 2014 Oct 13.
• Lembo AJ, Schneier HA, Shiff SJ, Kurtz CB, MacDougall JE, Jia XD, Shao JZ, Lavins BJ, Currie MG, Fitch DA, Jeglinski BI, Eng P, Fox SM, Johnston JM. Two randomized trials of linaclotide for chronic constipation. N Engl J Med. 2011 Aug 11;365(6):527-36. doi: 10.1056/NEJMoa1010863.

Study record dates

Study Major Dates

• Study Start: September 1, 2008
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): August 1, 2009

Study Registration Dates

• First Submitted: October 1, 2008
• First Submitted That Met QC Criteria: October 2, 2008
• First Posted (Estimate): October 3, 2008

Study Record Updates

• Last Update Posted (Estimate): January 30, 2013
• Last Update Submitted That Met QC Criteria: December 19, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Keywords: Constipation; Chronic Constipation; Linaclotide
• 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: LIN-MD-01