Trial of Linaclotide Administered to Patients With Irritable Bowel Syndrome With Constipation

A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial of Linaclotide Administered Orally for 12 Weeks Followed by a 4-Week Randomized Withdrawal Period in Patients With Irritable Bowel Syndrome With Constipation

The objective of this trial is to determine the efficacy and safety of linaclotide administered to patients with irritable bowel syndrome with constipation (IBS-C).

The primary efficacy parameter is the percentage of patients in each treatment group that meet the protocol definition for Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder.

Study Overview

• Status: Completed
• Conditions: Irritable Bowel Syndrome Characterized by Constipation
• Intervention / Treatment: Drug: Linaclotide 290 micrograms; Drug: Matching placebo

• Study Type: Interventional
• Enrollment (Actual): 803
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • Forest Investigative Site 107
    • New Market, Ontario, Canada, L3Y 7V1
      • Forest Investigative Site 112
    • Ottawa, Ontario, Canada, K2C 3R2
      • Forest Investigative Site 106
    • Sarnia, Ontario, Canada, N7T 4X3
      • Forest Investigative Site 115
    • Sudbury, Ontario, Canada, P3E 1H5
      • Forest Investigative Site 113
    • Toronto, Ontario, Canada, M3N 2V7
      • Forest Investigative Site 008
    • Toronto, Ontario, Canada, M4S 1Y2
      • Forest Investigative Site 116
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Forest Investigative Site 037
    • Birmingham, Alabama, United States, 35215
      • Forest Investigative Site 036
    • Hueytown, Alabama, United States, 35023
      • Forest Investigative Site 135
    • Huntsville, Alabama, United States, 35801
      • Forest Investigative Site 014
  • Arizona
    • Chandler, Arizona, United States, 85225
      • Forest Investigative Site 080
    • Mesa, Arizona, United States, 85210
      • Forest Investigative Site 053
    • Peoria, Arizona, United States, 85381
      • Forest Investigative Site 078
    • Phoenix, Arizona, United States, 85012
      • Forest Investigative Site 101
    • Phoenix, Arizona, United States, 85018
      • Forest Investigative Site 128
    • Scottsdale, Arizona, United States, 85251
      • Forest Investigative Site 051
    • Tucson, Arizona, United States, 85712
      • Forest Investigative Site 136
    • Tucson, Arizona, United States, 85741
      • Forest Investigative Site 087
  • California
    • Burbank, California, United States, 91505
      • Forest Investigative Site 094
    • Encinitas, California, United States, 92024
      • Forest Investigative Site 026
    • Foothill Ranch, California, United States, 92610
      • Forest Investigative Site 096
    • Los Angeles, California, United States, 90036
      • Forest Investigative Site 057
    • Mission Hills, California, United States, 91345
      • Forest Investigative Site 097
    • Orange, California, United States, 92869
      • Forest Investigative Site 005
    • Westlake Village, California, United States, 91361
      • Forest Investigative Site 024
  • Colorado
    • Boulder, Colorado, United States, 80304
      • Forest Investigative Site 021
    • Colorado Springs, Colorado, United States, 80907
      • Forest Investigative Site 019
    • Denver, Colorado, United States, 80205
      • Forest Investigative Site 034
    • Longmont, Colorado, United States, 80501
      • Forest Investigative Site 074
    • Wheat Ridge, Colorado, United States, 80033
      • Forest Investigative Site 010
  • Connecticut
    • Waterbury, Connecticut, United States, 06708
      • Forest Investigative Site 058
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Forest Investigative Site 042
    • Bradenton, Florida, United States, 34203
      • Forest Investigative Site 003
    • Brandon, Florida, United States, 33511
      • Forest Investigative Site 137
    • Brooksville, Florida, United States, 34613
      • Forest Investigative Site 070
    • Ft. Myers, Florida, United States, 33916
      • Forest Investigative Site 018
    • Jupiter, Florida, United States, 33458
      • Forest Investigative Site 030
    • Kissimmee, Florida, United States, 34741
      • Forest Investigative Site 077
    • Miami, Florida, United States, 33126
      • Forest Investigative Site 133
    • Miami, Florida, United States, 33143
      • Forest Investigative Site 031
    • New Smyrna Beach, Florida, United States, 32168
      • Forest Investigative Site 129
    • Ocala, Florida, United States, 34471
      • Forest Investigative Site 108
    • Orlando, Florida, United States, 32806
      • Forest Investigative Site 092
    • Panama City, Florida, United States, 32405
      • Forest Investigative Site 038
    • Pembroke Pines, Florida, United States, 33024
      • Forest Investigative Site 027
    • St. Petersburg, Florida, United States, 33709
      • Forest Investigative Site 045
    • Tampa, Florida, United States, 33606
      • Forest Investigative Site 015
    • Trinity, Florida, United States, 34655
      • Forest Investigative Site 104
    • Zephyrhills, Florida, United States, 33542
      • Forest Investigative Site 068
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Forest Investigative Site 032
    • Atlanta, Georgia, United States, 30342
      • Forest Investigative Site 103
    • Marietta, Georgia, United States, 30060
      • Forest Investigative Site 033
    • Marietta, Georgia, United States, 30067
      • Forest Investigative Site 020
    • Woodstock, Georgia, United States, 30189
      • Forest Investigative Site 040
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Forest Investigative Site 055
  • Illinois
    • Rockford, Illinois, United States, 61107
      • Forest Investigative Site 043
  • Indiana
    • Evansville, Indiana, United States, 47714
      • Forest Investigative Site 047
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Forest Investigative Site 046
  • Kansas
    • Arkansas City, Kansas, United States, 67005
      • Forest Investigative Site 029
    • Newton, Kansas, United States, 67114
      • Forest Investigative Site 009
    • Wichita, Kansas, United States, 67205
      • Forest Investigative Site 023
    • Wichita, Kansas, United States, 67207
      • Forest Investigative Site 093
  • Kentucky
    • Lexington, Kentucky, United States, 40509
      • Forest Investigative Site 067
    • Madisonville, Kentucky, United States, 42431
      • Forest Investigative Site 114
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Forest Investigative Site 132
    • Shreveport, Louisiana, United States, 71101
      • Forest Investigative Site 124
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Forest Investigative Site 013
    • Hagerstown, Maryland, United States, 21742
      • Forest Investigative Site 006
    • Lutherville, Maryland, United States, 21093
      • Forest Investigative Site 073
  • Massachusetts
    • Boston, Massachusetts, United States, 02135
      • Forest Investigative Site 001
  • Michigan
    • Kalamazoo, Michigan, United States, 49048
      • Forest Investigative Site 125
  • Minnesota
    • Chaska, Minnesota, United States, 55318
      • Forest Investigative Site 064
  • Missouri
    • St. Louis, Missouri, United States, 63128
      • Forest Investigative Site 004
  • New Jersey
    • Vineland, New Jersey, United States, 08360
      • Forest Investigative Site 085
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • Forest Investigative Site 052
  • New York
    • Brooklyn, New York, United States, 11214
      • Forest Investigative Site 035
    • Great Neck, New York, United States, 11021
      • Forest Investigative Site 017
    • Great Neck, New York, United States, 11023
      • Forest Investigative Site 011
    • Setauket, New York, United States, 11733
      • Forest Investigative Site 134
  • North Carolina
    • Boone, North Carolina, United States, 28607
      • Forest Investigative Site 122
    • Fayetteville, North Carolina, United States, 28304
      • Forest Investigative Site 072
    • Greensboro, North Carolina, United States, 27403
      • Forest Investigative Site 016
    • Hickory, North Carolina, United States, 28601
      • Forest Investigative Site 119
    • Raleigh, North Carolina, United States, 27612
      • Forest Investigative Site 088
    • Wilmington, North Carolina, United States, 28401
      • Forest Investigative Site 056
    • Winston-Salem, North Carolina, United States, 27103
      • Forest Investigative Site 065
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Forest Investigative Site 028
    • Cleveland, Ohio, United States, 44122
      • Forest Investigative Site 044
    • Columbus, Ohio, United States, 43215
      • Forest Investigative Site 123
    • Dayton, Ohio, United States, 45432
      • Forest Investigative Site 130
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Forest Investigative Site 082
    • Tulsa, Oklahoma, United States, 74135
      • Forest Investigative Site 102
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15206
      • Forest Investigative Site 039
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Forest Investigative Site 121
    • Greer, South Carolina, United States, 29651
      • Forest Investigative Site 069
    • Greer, South Carolina, United States, 29651
      • Forest Investigative Site 131
  • Tennessee
    • Nashville, Tennessee, United States, 37205
      • Forest Investigative Site 025
  • Texas
    • Austin, Texas, United States, 78705
      • Forest Investigative Site 099
    • Dallas, Texas, United States, 75234
      • Forest Investigative Site 002
    • Houston, Texas, United States, 77090
      • Forest Investigative Site 041
    • Houston, Texas, United States, 77090
      • Forest Investigative Site 110
    • Lake Jackson, Texas, United States, 77566
      • Forest Investigative Site 063
    • San Antonio, Texas, United States, 78209
      • Forest Investigative Site 095
    • San Antonio, Texas, United States, 78229
      • Forest Investigative Site 076
  • Utah
    • Salt Lake City, Utah, United States, 84102
      • Forest Investigative Site 089
    • Salt Lake City, Utah, United States, 84132
      • Forest Investigative Site 091
    • Salt Lake City, Utah, United States, 84148
      • Forest Investigative Site 100
  • Virginia
    • Charlottesville, Virginia, United States, 22911
      • Forest Investigative Site 054
    • Christianburg, Virginia, United States, 24073
      • Forest Investigative Site 061
    • Newport News, Virginia, United States, 23606
      • Forest Investigative Site 007
    • Norfolk, Virginia, United States, 23502
      • Forest Investigative Site 060
    • Norfolk, Virginia, United States, 23507
      • Forest Investigative Site 075
    • Richmond, Virginia, United States, 23294
      • Forest Investigative Site 050
  • Washington
    • Bellevue, Washington, United States, 98402
      • Forest Investigative Site 049
    • Lakewood, Washington, United States, 98499
      • Forest Investigative Site 098
    • Wenatchee, Washington, United States, 98801
      • Forest Investigative Site 066
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53209
      • Forest Investigative Site 083

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 meets protocol criteria for IBS: reports abdominal discomfort or pain that has two or more of the following three features:

  1. Relieved with defecation
  2. Onset associated with a change in frequency of stool
  3. Onset associated with a change in form (appearance) of stool
• Patient reports < 3 bowel movements (BMs) per week (in the absence of any laxative, suppository, or enema use during the preceding 24 hours) and reports straining, lumpy or hard stools, and/or sensation of incomplete evacuation during > 25% of BMs
• Patient has successfully completed protocol procedures (with no clinically significant findings): physical exam, 12-lead ECG, or clinical laboratory tests (some patients may require a colonoscopy per American Gastroenterological Association (AGA) guidelines)
• Patient is compliant with Interactive Voice Response System (IVRS) for daily diary reporting of BM habits and IBS symptoms

Exclusion Criteria:

• Patient has history of loose or watery stools for >25% of BMs
• Patient has a structural abnormality of the gastrointestinal (GI) tract or a history of a disease or condition that can affect GI motility
• Patient has any protocol-excluded or clinically significant medical or surgical history or concomitant medication use 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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching placebo	Drug: Matching placebo; Oral, once daily each morning at least 30 minutes before breakfast for the duration of the study
Experimental: Linaclotide; Linaclotide 290 micrograms	Drug: Linaclotide 290 micrograms; 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) 3+1 Responder, 9 Out of 12 Weeks	A patient is considered to be a CSBM 3+1 responder if, for at least 9 out of the 12 weeks of the treatment period, the patient had at least 3 CSBMs and experienced an increase of at least 1 CSBM from baseline during a particular week. 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
Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 9 Out of 12 Weeks	A patient is considered to be an APC responder if, for at least 9 out of the 12 weeks of the treatment period, the patient had at least 3 CSBMs, experienced an increase of at least 1 CSBM from baseline, and experienced a decrease of at least 30 percent in their Abdominal Pain (AP) score from baseline during a particular week. The AP score assesses the worst of a patient's AP in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no AP and 10 represents very severe AP. A CSBM is defined as a spontaneous bowel movement, associated with a sense of complete evacuation.	Change from Baseline to Week 12
Abdominal Pain Responder, 9 Out of 12 Weeks	A patient is considered to be an abdominal pain responder if, for at least 9 out of the 12 weeks of the treatment period, they experienced a decrease of at least 30 percent in the mean abdominal pain score from baseline during a particular week. The Abdominal Pain score assesses the worst of a patient's abdominal pain in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no abdominal pain and 10 represents very severe abdominal pain.	Change from Baseline to Week 12
Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 6 Out of 12 Weeks.	A patient is considered an APC responder if, for at least 6 of the 12 weeks of the treatment, the patient experienced an increase of at least 1 Complete Spontaneous Bowel Movement (CSBM) from baseline and experienced a decrease of at least 30 percent in their Abdominal Pain (AP)score during a particular week. The AP score assesses the worst of a patient's AP in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no AP and 10 represents very severe AP. A CSBM was defined as a Spontaneous Bowel Movement (SBM) that was associated with a sense of complete evacuation.	Change from Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
12-Week Change in Abdominal Pain Score	Abdominal Pain at its worst (in the last 24 hours) is based on an 11-point scale where 0 represents no abdominal pain and 10 represents very severe abdominal pain.	Change from Baseline to Week 12
12-Week Change in Bloating	Bloating was assessed on an 11-point scale where a value of 0 is "none" and a value of 10 is "very severe".	Change from Baseline to Week 12
Complete Spontaneous Bowl Movement (CSBM) Responder for 6 Weeks Out of 12 Weeks of Treatment	A patient is considered to be a CSBM responder if, for at least 6 out of the 12 weeks of the treatment period, an increase of at least 1 CSBM per week from baseline was experienced.	Change from Baseline to Week 12
12-Week Complete Spontaneous Bowel Movement (CSBM) Frequency Rate	The number of CSBMs per week.	Change from Baseline to Week 12
12-Week Spontaneous Bowl Movement (SBM) Frequency Rate	The number of Spontaneous Bowl Movements experienced per week.	Change from Baseline to Week 12
12-Week Stool Consistency	The consistency of each BM was assessed by patients using the 7-point Bristol Stool Form Scale (BSFS) from 1 to 7.; = 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 Change in Abdominal Discomfort	Abdominal Discomfort is measured on an 11-point scale where a value of 0 is "none" and a value of 10 is "very severe."	Change from Baseline to Week 12
Abdominal Pain Responder for 6 Out of 12 Weeks	A patient is considered to be an abdominal pain responder if, for at least 6 out of the 12 weeks of the treatment period, they experienced a decrease of 30 percent or more in the abdominal pain score from baseline. The Abdominal Pain score assesses the worst of a patient's abdominal pain in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no abdominal pain and 10 represents very severe abdominal pain.	Change from Baseline to Week 12
12-Week Percent of Abdominal Pain-free (APF) Days	Abdominal pain free (APF) days are those days where the patient reported a score of '0' for abdominal pain at its worst Abdominal Pain at its worst (in the last 24 hours) is based on an 11-point scale where 0 represents no abdominal pain and 10 represents very severe abdominal pain.	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 Research Institute, a subsidiary of Forest Laboratories Inc.

Publications and helpful links

General Publications

• Rao SS, Quigley EM, Shiff SJ, Lavins BJ, Kurtz CB, MacDougall JE, Currie MG, Johnston JM. Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation. Clin Gastroenterol Hepatol. 2014 Apr;12(4):616-23. doi: 10.1016/j.cgh.2013.09.022. Epub 2013 Sep 25.
• Quigley EM, Tack J, Chey WD, Rao SS, Fortea J, Falques M, Diaz C, Shiff SJ, Currie MG, Johnston JM. Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints. Aliment Pharmacol Ther. 2013 Jan;37(1):49-61. doi: 10.1111/apt.12123. Epub 2012 Nov 1.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): August 1, 2010

Study Registration Dates

• First Submitted: July 28, 2009
• First Submitted That Met QC Criteria: July 28, 2009
• First Posted (Estimate): July 29, 2009

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: Irritable Bowel Syndrome; Constipation; Linaclotide
• 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: LIN-MD-31