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

Forest Laboratories

Status and phase: Completed; Phase 4

Conditions: Irritable Bowel Syndrome With Constipation; Chronic Idiopathic Constipation

Treatments: Drug: Linaclotide

Study type: Interventional

Funder types: Industry

Identifiers

NCT02590432

LIN-MD-10

Details and patient eligibility

About

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.

Full 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.

Enrollment: 828 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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828 participants in 9 patient groups

LINZESS® 145 μg (CIC, Open Label)

Experimental group

Description:

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.

Treatment:

Drug: Linaclotide

LINZESS® 290 μg (IBS-C, Open Label)

Experimental group

Description:

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.

Treatment:

Drug: Linaclotide

LINZESS® 290 μg (IBS-C, Double Blind)

Experimental group

Description:

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.

Treatment:

Drug: Linaclotide

LINZESS® 145 μg (IBS-C, Double Blind)

Experimental group

Description:

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.

Treatment:

Drug: Linaclotide

LINZESS® 72 μg (IBS-C, Double Blind)

Experimental group

Description:

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.

Treatment:

Drug: Linaclotide

LINZESS® 145 μg (CIC, Double Blind)

Experimental group

Description:

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.

Treatment:

Drug: Linaclotide

LINZESS® 72 μg (CIC, Double Blind)

Experimental group

Description:

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.

Treatment:

Drug: Linaclotide

LINZESS® 72 μg (CIC, Dose-reduced Open Label)

Experimental group

Description:

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.

Treatment:

Drug: Linaclotide

LINZESS® 72 μg (IBS-C, Dose-reduced Open Label)

Experimental group

Description:

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.

Treatment:

Drug: Linaclotide