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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Irritable Bowel Syndrome With Constipation, Chronic Idiopathic Constipation

Intervention / Treatment
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* Drug: Linaclotide


Participation Criteria
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Eligibility Criteria
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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: Improvement with defecation. Onset associated with a change in frequency of stool. 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: Straining during at least 25% of defecations. Lumpy or hard stools in at least 25% of defecations. Sensation of incomplete evacuation for at least 25% of defecations. Sensation of anorectal obstruction/blockage for at least 25% of defecations. Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LINZESS® 145 μg (CIC, Open Label)<br>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<br>* Linaclotide capsules, orally, once daily.<br>* Other names: LINZESS®;|
| Experimental: LINZESS® 290 μg (IBS-C, Open Label)<br>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<br>* Linaclotide capsules, orally, once daily.<br>* Other names: LINZESS®;|
| Experimental: LINZESS® 290 μg (IBS-C, Double Blind)<br>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<br>* Linaclotide capsules, orally, once daily.<br>* Other names: LINZESS®;|
| Experimental: LINZESS® 145 μg (IBS-C, Double Blind)<br>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<br>* Linaclotide capsules, orally, once daily.<br>* Other names: LINZESS®;|
| Experimental: LINZESS® 72 μg (IBS-C, Double Blind)<br>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<br>* Linaclotide capsules, orally, once daily.<br>* Other names: LINZESS®;|
| Experimental: LINZESS® 145 μg (CIC, Double Blind)<br>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<br>* Linaclotide capsules, orally, once daily.<br>* Other names: LINZESS®;|
| Experimental: LINZESS® 72 μg (CIC, Double Blind)<br>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<br>* Linaclotide capsules, orally, once daily.<br>* Other names: LINZESS®;|
| Experimental: LINZESS® 72 μg (CIC, Dose-reduced Open Label)<br>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<br>* Linaclotide capsules, orally, once daily.<br>* Other names: LINZESS®;|
| Experimental: LINZESS® 72 μg (IBS-C, Dose-reduced Open Label)<br>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<br>* Linaclotide capsules, orally, once daily.<br>* Other names: LINZESS®;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunogenicity, Irritable Bowel Syndrome with Constipation, Chronic Idiopathic Constipation, Linaclotide, Linzess