Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial of Linaclotide Administered to Patients With Opioid-Induced Constipation Receiving Chronic Opioid Treatment for Non-Cancer Pain

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the safety and efficacy of linaclotide for the treatment of opioid-induced constipation (OIC), in adults receiving stable opioid treatment for chronic non-cancer pain that has been present for a minimum of 3 months. This study included up to a 4-week Screening Period, and a 2 to 3-week Pretreatment Period. Patients meeting the entry criteria were randomized to 1 of 2 doses of linaclotide or placebo once per day for 8 weeks. This 8-week study assessed the effects of linaclotide on bowel movement frequency, as well as other bowel symptoms of OIC.

Official Title
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A Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial of Linaclotide Administered Orally for 8 Weeks to Adult Outpatients With Opioid-Induced Constipation Receiving Chronic Opioid Treatment for Non-Cancer Pain

Conditions
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Opioid-Induced Constipation

Intervention / Treatment
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* Drug: Linaclotide 145 micrograms
* Drug: Linaclotide 290 micrograms
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has chronic non-cancer pain that has been present for a minimum of 3 months Patient has been receiving a stable oral dose of a full-opioid agonist for at least 4 days per week during the 8 consecutive weeks Patient meets protocol criteria for Opioid-Induced Constipation (OIC): < 3 spontaneous bowel movements (SBMs) per week and reports one of the following symptoms for at least 4 weeks: Straining during > 25% of BMs Lumpy or hard stools during > 25% of BMs Sensation of incomplete evacuation during > 25% of BMs Patient meets the colonoscopy requirements defined by the American Gastroenterological Association guidelines Patient has successfully completed protocol procedures (with no clinically significant findings) Patient is compliant with Interactive Voice Response System (IVRS) for daily diary reporting Patient has a total of < 6 SBMs in IVRS during the 14 days before and up to the time of Randomization Patient has adequate relief and well-controlled pain with current dose of opioid Exclusion Criteria: Patient has been using opioids for abdominal pain Patient has symptoms of or been diagnosed with chronic constipation or chronic idiopathic constipation prior to initiation of opioid treatment Patient has symptoms of or been diagnosed with Irritable Bowel Syndrome (IBS) prior to initiation of opioid treatment Patient has a history of loose or watery stools for > 25% of BMs during the 3 months before the Screening in the absence of laxatives, suppositories, or enemas Patient has a structural abnormality of the gastrointestinal (GI) tract or a disease or condition that can affect GI motility Patient 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

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Linaclotide 145 micrograms<br>Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. | Drug: Linaclotide 145 micrograms<br> <br> * Other names: Linzess;|
| Experimental: Linaclotide 290 micrograms<br>Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. | Drug: Linaclotide 290 micrograms<br> <br> * Other names: Linzess;|
| Experimental: Placebo<br>Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. | Drug: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 8-Week SBM Frequency Rate (SBMs/Week) | Change from baseline in 8-Week SBM frequency rate (SBMs/week) during the Treatment Period. | Baseline (Week 0) to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First SBM After the First Dose of Investigational Product | The median time to the first SBM after the first dose of investigational product | Baseline (Day 0) up to 8 weeks | 
| Percentage of Participants Meeting 6/8 Week Spontaneous Bowel Movement (SBM) 3 + 1 Responder Criteria | A 6/8 Week SBM 3 + 1 responder was a participant who met the weekly SBM 3 + 1 responder criteria for at least 6 out of the 8 weeks of the Treatment Period. For each week in the Treatment Period, a weekly SBM 3 + 1 responder was a patient who had an SBM weekly rate ≥ 3 and an increase ≥ 1 in the SBM weekly rate from baseline for that week. | 8-week treatment period | 
| Change From Baseline in 8-Week Stool Consistency | Stool Consistency was assessed using the 7-Point Bristol Stool Form Scale: = 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 = watery, no solid pieces (entirely liquid) | Baseline (Week 0) to Week 8 | 
| Change From Baseline in 8-Week Straining | Straining was measured on a 5-point ordinal scale where a value of 1 is not at all and a value of 5 is an extreme amount. | Baseline (Week 0) to Week 8 | 
| Change From Baseline in 8-Week Abdominal Bloating | Abdominal bloating was collected daily via IVRS calls and measured using an 11-point numerical rating scale, where 0 represents no abdominal bloating and 10 represents very severe abdominal bloating. | Baseline (Week 0) to Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opioid-Induced Constipation, Linaclotide, Linzess