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

Chronic Idiopathic Constipation Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02590432
• Other study ID #: LIN-MD-10
• Status: Completed
• Phase: Phase 4
• Start date: November 1, 2015
• Est. completion date: February 5, 2018

Study information

• Verified date: August 2019
• Source: Forest Laboratories
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 828
• Est. completion date: February 5, 2018
• Est. primary completion date: February 5, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Idiopathic Constipation
• Constipation
• Irritable Bowel Syndrome
• Irritable Bowel Syndrome With Constipation
• Syndrome

Intervention

Drug:
• Linaclotide
Linaclotide capsules, orally, once daily.

Locations

Country	Name	City	State
United States	Albuquerque Clinical Trials	Albuquerque	New Mexico
United States	Lovelace Scientific Resources, Inc.	Albuquerque	New Mexico
United States	Pinnacle Research Group, LLC	Anniston	Alabama
United States	North Alabama Research Center, LLC	Athens	Alabama
United States	The Center for Clinical Trials, Inc.	Biloxi	Mississippi
United States	River Birch Research Alliance, LLC	Blue Ridge	Georgia
United States	Northwest Clinical Trials	Boise	Idaho
United States	ZASA Clinical Research	Boynton Beach	Florida
United States	Meridien Research	Bradenton	Florida
United States	Clinical Research of Brandon LLC	Brandon	Florida
United States	Radiant Research, Inc.	Chandler	Arizona
United States	UNC Health Care, University of North Carolina Medical Center, Memorial Hospital	Chapel Hill	North Carolina
United States	Charlottesville Medical Research Center, LLC	Charlottesville	Virginia
United States	Alliance Clinical Research	Childersburg	Alabama
United States	New Horizons Clinical Research	Cincinnati	Ohio
United States	Iowa Digestive Center, PC	Clive	Iowa
United States	Kindred Medical Institute for Clinical Trials, LLC	Corona	California
United States	Global Clinical Trials LLC	Costa Mesa	California
United States	Partners In Clinical Research	Cumberland	Rhode Island
United States	Clinical Inquest Center LTD	Dayton	Ohio
United States	Dayton Gastroenterology, Inc.	Dayton	Ohio
United States	Lynn Institute of Denver	Denver	Colorado
United States	Diagnamics Inc	Encinitas	California
United States	Aa Mrc Llc	Flint	Michigan
United States	G & L Research, LLC	Foley	Alabama
United States	Clinical Physiology Associates	Fort Myers	Florida
United States	MD Studies, Inc.	Fountain Valley	California
United States	Research Center of Fresno, Inc.	Fresno	California
United States	VVCRD Clinical Research	Garden Grove	California
United States	PharmQuest	Greensboro	North Carolina
United States	Greenville Pharmaceutical Research, Inc.	Greenville	South Carolina
United States	Radiant Research, Inc.	Greer	South Carolina
United States	Drug Trials America	Hartsdale	New York
United States	Direct Helpers Research Center	Hialeah	Florida
United States	Eastern Research, Inc.	Hialeah	Florida
United States	Houston Endoscopy & Research Center	Houston	Texas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	The Clinical Trial Center, LLC	Jenkintown	Pennsylvania
United States	Beyer Research	Kalamazoo	Michigan
United States	Northstate Clinical Research	Lenoir	North Carolina
United States	Applied Research Center of Arkansas	Little Rock	Arkansas
United States	Preferred Research Partners, Inc.	Little Rock	Arkansas
United States	Center for Advanced Gastroenterology	Maitland	Florida
United States	Clinical Neuroscience Solutions, Inc.	Memphis	Tennessee
United States	Florida Medical Center and Research, Inc.	Miami	Florida
United States	Facey Medical Foundation	Mission Hills	California
United States	KAMP Medical Research Inc	Natchitoches	Louisiana
United States	Manhattan Medical Research Practice PLLC	New York	New York
United States	Heartland Research Associates, LLC	Newton	Kansas
United States	DiGiovanna Institute for Medical Education & Research	North Massapequa	New York
United States	IPS Research Company	Oklahoma City	Oklahoma
United States	Clinical Neuroscience Solutions, Inc	Orlando	Florida
United States	Temple University	Philadelphia	Pennsylvania
United States	Preferred Primary Care Physicians, INC	Pittsburgh	Pennsylvania
United States	Research Across America	Plano	Texas
United States	Accord Clinical Research	Port Orange	Florida
United States	Health Science Research Center	Pratt	Kansas
United States	Digestive Health Associates	Reno	Nevada
United States	Rockford Gastroenterology Associates	Rockford	Illinois
United States	Clinical Trials Research	Sacramento	California
United States	Northern California Research	Sacramento	California
United States	Sundance Clinical Research, LLC	Saint Louis	Missouri
United States	Meridien Research	Saint Petersburg	Florida
United States	Sun Research Institute	San Antonio	Texas
United States	Artemis Institute for Clinical Research	San Diego	California
United States	Precision Research Institute	San Diego	California
United States	Radiant Research, Inc.	Scottsdale	Arizona
United States	Montgomery Medical, Inc.	Smithfield	Pennsylvania
United States	Coastal Research Associates, Inc.	South Weymouth	Massachusetts
United States	Clinical Research Institute of Arizona, LLC	Surprise	Arizona
United States	Clinical Research Consortium	Tempe	Arizona
United States	Desert Sun Clinical Research, LLC.	Tucson	Arizona
United States	Empire Clinical Research	Upland	California
United States	Bay State Clinical Trials, Inc.	Watertown	Massachusetts
United States	Integrated Clinical Trial Services, Inc.	West Des Moines	Iowa
United States	Heartland Research Associates, LLC	Wichita	Kansas
United States	Heartland Research Associates, LLC	Wichita	Kansas
United States	Digestive Health Specialists, PA	Winston-Salem	North Carolina
United States	North Georgia Clinical Research	Woodstock	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Forest Laboratories	Ironwood Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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