An Open-Label, Long-term Study to Assess the Immunogenicity of LINZESS® (Linaclotide) Administered Orally to Adult Participants With Irritable Bowel Syndrome With Constipation or Chronic Idiopathic Constipation

An Open-label, Long-term Study to Assess the Immunogenicity of Linaclotide Administered Orally to Adult Patients With Irritable Bowel Syndrome With Constipation or Chronic Idiopathic Constipation.

The primary objective of this study is to assess the potential of LINZESS® (linaclotide) treatment to induce the development of anti-drug antibodies (ADAs). The secondary objectives are to provide additional evidence supporting the long-term safety and efficacy of linaclotide in adult irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) participants and to evaluate lower doses of linaclotide.

Study Overview

• Status: Completed
• Conditions: Irritable Bowel Syndrome With Constipation; Chronic Idiopathic Constipation
• Intervention / Treatment: Drug: Linaclotide

Detailed Description

This study includes up to a 3-week Screening Period, followed by a 52-week treatment period. Participants with CIC meeting the entry criteria received linaclotide 145 μg capsules, orally, once daily and participants with IBS-C meeting the entry criteria received linaclotide 290 μg capsules, orally, once daily. Participants with intolerable Adverse Events (AEs), following resolution of the AEs, could be randomized to receive 290 μg, 145 μg, or the lower dose of 72 μg linaclotide oral capsules for IBS-C; and 145 μg or 72 μg for CIC. Participants who experienced further intolerable AEs after the randomization could be transitioned to open-label 72 μg linaclotide.

• Study Type: Interventional
• Enrollment (Actual): 828
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Pinnacle Research Group, LLC
    • Athens, Alabama, United States, 35611
      • North Alabama Research Center, LLC
    • Childersburg, Alabama, United States, 35044
      • Alliance Clinical Research
    • Foley, Alabama, United States, 36535
      • G & L Research, LLC
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Radiant Research, Inc.
    • Scottsdale, Arizona, United States, 85251
      • Radiant Research, Inc.
    • Surprise, Arizona, United States, 85374
      • Clinical Research Institute of Arizona, LLC
    • Tempe, Arizona, United States, 85283
      • Clinical Research Consortium
    • Tucson, Arizona, United States, 85710
      • Desert Sun Clinical Research, LLC.
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Preferred Research Partners, Inc.
    • Little Rock, Arkansas, United States, 72212
      • Applied Research Center of Arkansas
  • California
    • Corona, California, United States, 92879
      • Kindred Medical Institute for Clinical Trials, LLC
    • Costa Mesa, California, United States, 92627
      • Global Clinical Trials LLC
    • Encinitas, California, United States, 92024
      • Diagnamics Inc
    • Fountain Valley, California, United States, 92708
      • MD Studies, Inc.
    • Fresno, California, United States, 93702
      • Research Center of Fresno, Inc.
    • Garden Grove, California, United States, 92845
      • VVCRD Clinical Research
    • Mission Hills, California, United States, 91345
      • FACEY Medical Foundation
    • Sacramento, California, United States, 95821
      • Northern California Research
    • Sacramento, California, United States, 95821
      • Clinical Trials Research
    • San Diego, California, United States, 92103
      • Artemis Institute for Clinical Research
    • San Diego, California, United States, 92114
      • Precision Research Institute
    • Upland, California, United States, 91786
      • Empire Clinical Research
  • Colorado
    • Denver, Colorado, United States, 80246
      • Lynn Institute of Denver
  • Florida
    • Boynton Beach, Florida, United States, 33472
      • Zasa Clinical Research
    • Bradenton, Florida, United States, 34201
      • Meridien Research
    • Brandon, Florida, United States, 33511
      • Clinical Research of Brandon LLC
    • Fort Myers, Florida, United States, 33912
      • Clinical Physiology Associates
    • Hialeah, Florida, United States, 33012
      • Direct Helpers Research Center
    • Hialeah, Florida, United States, 33013
      • Eastern Research, Inc.
    • Maitland, Florida, United States, 32751
      • Center For Advanced Gastroenterology
    • Miami, Florida, United States, 33142
      • Florida Medical Center and Research, Inc.
    • Orlando, Florida, United States, 32801
      • Clinical Neuroscience Solutions, Inc
    • Port Orange, Florida, United States, 32129
      • Accord Clinical Research
    • Saint Petersburg, Florida, United States, 33709
      • Meridien Research
  • Georgia
    • Blue Ridge, Georgia, United States, 30513
      • River Birch Research Alliance, LLC
    • Woodstock, Georgia, United States, 30189
      • North Georgia Clinical Research
  • Idaho
    • Boise, Idaho, United States, 83704
      • Northwest Clinical Trials
  • Illinois
    • Rockford, Illinois, United States, 611047
      • Rockford Gastroenterology Associates
  • Iowa
    • Clive, Iowa, United States, 50325
      • Iowa Digestive Center, PC
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
    • West Des Moines, Iowa, United States, 50265
      • Integrated Clinical Trial Services, Inc.
  • Kansas
    • Newton, Kansas, United States, 67114
      • Heartland Research Associates, LLC
    • Pratt, Kansas, United States, 67124
      • Health Science Research Center
    • Wichita, Kansas, United States, 67205
      • Heartland Research Associates, LLC
    • Wichita, Kansas, United States, 67207
      • Heartland Research Associates, LLC
  • Louisiana
    • Natchitoches, Louisiana, United States, 71457
      • KAMP Medical Research Inc
  • Massachusetts
    • South Weymouth, Massachusetts, United States, 02190
      • Coastal Research Associates, Inc.
    • Watertown, Massachusetts, United States, 02472
      • Bay State Clinical Trials, Inc.
  • Michigan
    • Flint, Michigan, United States, 48503
      • Aa Mrc Llc
    • Kalamazoo, Michigan, United States, 49009
      • Beyer Research
  • Mississippi
    • Biloxi, Mississippi, United States, 39531
      • The Center for Clinical Trials, Inc.
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Sundance Clinical Research, LLC
  • Nevada
    • Reno, Nevada, United States, 89511
      • Digestive Health Associates
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Albuquerque Clinical Trials
    • Albuquerque, New Mexico, United States, 87108
      • Lovelace Scientific Resources, Inc.
  • New York
    • Hartsdale, New York, United States, 10530
      • Drug Trials America
    • New York, New York, United States, 10016
      • Manhattan Medical Research Practice PLLC
    • North Massapequa, New York, United States, 11758-1802
      • DiGiovanna Institute for Medical Education & Research
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Health Care, University of North Carolina Medical Center, Memorial Hospital
    • Greensboro, North Carolina, United States, 27408
      • PharmQuest
    • Lenoir, North Carolina, United States, 38645
      • Northstate Clinical Research
    • Winston-Salem, North Carolina, United States, 27103
      • Digestive Health Specialists, PA
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • New Horizons Clinical Research
    • Dayton, Ohio, United States, 45419
      • Clinical Inquest Center Ltd
    • Dayton, Ohio, United States, 45440
      • Dayton Gastroenterology, Inc.
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • IPS Research Company
  • Pennsylvania
    • Jenkintown, Pennsylvania, United States, 19046
      • The Clinical Trial Center, LLC
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University
    • Pittsburgh, Pennsylvania, United States, 15236
      • Preferred Primary Care Physicians, Inc
    • Smithfield, Pennsylvania, United States, 15478
      • Montgomery Medical, Inc.
  • Rhode Island
    • Cumberland, Rhode Island, United States, 02864
      • Partners in Clinical Research
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Greenville Pharmaceutical Research, Inc.
    • Greer, South Carolina, United States, 29651
      • Radiant Research, Inc.
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Clinical Neuroscience Solutions, Inc.
  • Texas
    • Houston, Texas, United States, 77079
      • Houston Endoscopy & Research Center
    • Plano, Texas, United States, 75093
      • Research Across America
    • San Antonio, Texas, United States, 78125
      • Sun Research Institute
  • Virginia
    • Charlottesville, Virginia, United States, 22911
      • Charlottesville Medical Research Center, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants meet the Rome III criteria for IBS-C or CIC:
• IBS-C Criteria: the participant must meet the following 2 criteria (A and B).

A. IBS Criteria: The participant must have abdominal pain or discomfort at least 3 days per month in the 3 months before diagnosis (with symptom onset at least 6 months before diagnosis) associated with 2 or more of the following:

1. Improvement with defecation.
2. Onset associated with a change in frequency of stool.

3. Onset associated with a change in form (appearance) of stool. B. Stool Consistency Requirement: During the 3 months before diagnosis in the absence of laxative or enema use, the patient has hard or lumpy stools (Bristol Stool Form Scale [BSFS] score 1 or 2) with at least 25% of bowel movements (BMs) and has loose or mushy stools (BSFS 5 or 6) with <25% of BMs.

   • CIC Criteria: the participant must meet the following 3 criteria (A, B, and C):

A. Participant meets 2 or more of the following criteria for 3 months before the diagnosis with symptom onset at least 6 months before diagnosis:

1. Straining during at least 25% of defecations.
2. Lumpy or hard stools in at least 25% of defecations.
3. Sensation of incomplete evacuation for at least 25% of defecations.
4. Sensation of anorectal obstruction/blockage for at least 25% of defecations.
5. Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor).

6. Fewer than 3 defecations per week. B. Loose stools are rarely present without the use of laxatives. C. Insufficient criteria for irritable bowel syndrome. (The criteria for IBS are provided in Point A under IBS Criteria, above).

   • Participant meets the colonoscopy requirements, which are modified from the Summary of the US-Multi-Society Task Force on Colorectal Cancer and other Colonoscopy Requirements.
   • Participant has successfully completed protocol procedures (with no clinically significant findings).

Exclusion Criteria:

• At Day 1 visit, the participant reports having 6 or more spontaneous bowel movements (SBMs) in the week prior to screening.
• At Day 1 visit, the participant reports having any SBMs that were watery (BSFS=7) or more than 1 SBM that was mushy (BSFS=6) in the week prior to screening.
• Participant has a structural abnormality of the gastrointestinal (GI) tract or a disease or condition that can affect GI motility.
• Participant 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.
• Participant has ever received linaclotide as a treatment (including commercially-available product) or has been randomized into any clinical study in which linaclotide was a treatment. (participant who enrolled into linaclotide clinical studies conducted prior or during this study but failed to be randomized are eligible for the current study).
• Participant has ever received plecanatide, SP-333, or has participated in a plecanatide clinical study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LINZESS® 145 μg (CIC, Open Label); LINZESS® (linaclotide) 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	Drug: Linaclotide; Linaclotide capsules, orally, once daily.; Other Names: LINZESS®
Experimental: LINZESS® 290 μg (IBS-C, Open Label); LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period.	Drug: Linaclotide; Linaclotide capsules, orally, once daily.; Other Names: LINZESS®
Experimental: LINZESS® 290 μg (IBS-C, Double Blind); Following participation in the Open Label Treatment Period, LINZESS® 290 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was reduced to Open Label 72 μg, if applicable.	Drug: Linaclotide; Linaclotide capsules, orally, once daily.; Other Names: LINZESS®
Experimental: LINZESS® 145 μg (IBS-C, Double Blind); Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was reduced to Open Label 72 μg, if applicable.	Drug: Linaclotide; Linaclotide capsules, orally, once daily.; Other Names: LINZESS®
Experimental: LINZESS® 72 μg (IBS-C, Double Blind); Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	Drug: Linaclotide; Linaclotide capsules, orally, once daily.; Other Names: LINZESS®
Experimental: LINZESS® 145 μg (CIC, Double Blind); Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable.	Drug: Linaclotide; Linaclotide capsules, orally, once daily.; Other Names: LINZESS®
Experimental: LINZESS® 72 μg (CIC, Double Blind); Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable.	Drug: Linaclotide; Linaclotide capsules, orally, once daily.; Other Names: LINZESS®
Experimental: LINZESS® 72 μg (CIC, Dose-reduced Open Label); Following participation in the Double-blind Treatment Period, if an intolerable AE occurred, LINZESS® 72 μg capsules, orally, once daily up to Week 52 for participants with CIC.	Drug: Linaclotide; Linaclotide capsules, orally, once daily.; Other Names: LINZESS®
Experimental: LINZESS® 72 μg (IBS-C, Dose-reduced Open Label); Following participation in the Double-blind Treatment Period, if an intolerable AE occurred, LINZESS® 72 μg capsules, orally, once daily up to Week 52 for participants with IBS-C.	Drug: Linaclotide; Linaclotide capsules, orally, once daily.; Other Names: LINZESS®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Positive Treatment-Related Anti-Drug Antibodies (ADA) in Serum	Participants who met either of the following criteria: 1) treatment-induced ADA-positive (≥ 1 postbaseline ADA-positive sample) for baseline ADA negative or ADA-undetermined participants or 2) treatment-boosted ADA-positive (≥ 1 postbaseline ADA-positive sample with titer values ≥ 4-fold the baseline titer value) for baseline ADA-positive participants were reported as a ADA positive responder.	Baseline (Day 1) up to 52 weeks or 8 months post last dose if ADA positive at Week 52 (approximately 84 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Participant's Assessment of Constipation Severity	Participants rated constipation severity during the previous 7 days on a 5-point ordinal scale where, 1=None, 2=Mild, 3=Moderate, 4=Severe and 5=Very Severe. Higher scores indicate greater severity. A negative change from Baseline indicates improvement.	Baseline (Day 1) to Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period)
Change From Baseline in Participant Assessment of Irritable Bowel Syndrome (IBS) Symptom Severity for Participants With Irritable Bowel Syndrome With Constipation (IBS-C)	Participants rated IBS symptoms severity during the previous 7 days on a 5-point ordinal scale where, 1=None, 2=Mild, 3=Moderate, 4=Severe and 5=Very severe. Higher scores indicate greater severity. A negative change from Baseline indicates improvement.	Baseline (Day 1) to Week 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period)
Change From Baseline in Degree of Relief of IBS Symptoms for Participants With IBS-C	Participants rated degree of relief of IBS symptoms during previous 7 days on a 7-point balanced ordinal scale where, 1=completely relieved, 2=considerably relieved, 3=somewhat relieved, 4=unchanged, 5=somewhat worse, 6=considerably worse and 7=as bad as I can imagine. Lower scores indicate greater relief. A negative change from Baseline indicates improvement.	Baseline (Day 1) to Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period)
IBS Treatment Satisfaction Assessment Postbaseline for Participants With IBS-C	Participants rated degree of satisfaction with the LINZESS®'s ability to relieve IBS symptoms on a 5-point ordinal scale where, 1=Not at all satisfied, 2=A little satisfied, 3=Moderately satisfied, 4=Quite satisfied and 5=Very satisfied. Higher scores indicate greater satisfaction.	Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period)
Constipation Treatment Satisfaction Assessment Postbaseline for Participants With Chronic Idiopathic Constipation (CIC)	Participants rated degree of satisfaction with LINZESS®'s ability to relieve constipation symptoms on a 5-point ordinal scale where 1=Not at all satisfied, 2=A little satisfied, 3=Moderately satisfied, 4=Quite satisfied and 5=Very satisfied. Higher scores indicate greater satisfaction.	Weeks 2, 4, 12, 26, 40 and 52 (Open Label Treatment Period)
Number of Participants With Recurrence of Diarrhea	Participant reporting any instance of diarrhea during the Double-blind Treatment Period.	From first dose in the Double-blind Treatment Period to Week 52
Number of Participants With Recurrence of Intolerable Diarrhea	Participants reporting any instance of intolerable diarrhea during the Double-blind Treatment Period (Non-responder otherwise). Only includes participants reporting intolerable diarrhea during the Open-label Treatment Period.	From first dose in the Double-blind Treatment Period to Week 52
Percentage of Participants With Treatment Emergent Adverse Events (TEAE)	An adverse event is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is an AE that occurred after receiving the first dose of investigational product or an AE present prior to first dose but increased in severity during the Treatment Period.	From first dose of study treatment up to Week 52
Time to First Recurrence of Diarrhea	Time to first recurrence of diarrhea was defined as event/censored date - double-blind start date + 1, where event date (responders) = first recurrence of diarrhea date during the double-blind treatment period; censoring date (non-responders) = double-blind end date. Only includes participants reporting intolerable diarrhea during the open-label treatment period.	From first dose in the Double-blind Treatment Period to Week 52
Time to First Recurrence of Intolerable Diarrhea	Time to first recurrence of intolerable diarrhea was defined as event/censored date - double-blind start date + 1, where event date (responders) = first recurrence of intolerable diarrhea date during the double-blind treatment period; censoring date (non-responders) = double-blind end date. Only includes participants reporting intolerable diarrhea during the open-label treatment period.	From first dose in the Double-blind Treatment Period to Week 52

Collaborators and Investigators

• Sponsor: Forest Laboratories
• Collaborators: Ironwood Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): February 5, 2018
• Study Completion (Actual): February 5, 2018

Study Registration Dates

• First Submitted: October 27, 2015
• First Submitted That Met QC Criteria: October 27, 2015
• First Posted (Estimate): October 29, 2015

Study Record Updates

• Last Update Posted (Actual): August 22, 2019
• Last Update Submitted That Met QC Criteria: August 8, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Immunogenicity; Irritable Bowel Syndrome with Constipation; Linzess; Linaclotide; Chronic Idiopathic Constipation
• 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-10