Trial of Linaclotide Administered to Patients With Irritable Bowel Syndrome With Constipation

Study Overview
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Brief Summary
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The objective of this trial is to determine the efficacy and safety of linaclotide administered to patients with irritable bowel syndrome with constipation (IBS-C). The primary efficacy parameter is the percentage of patients in each treatment group that meet the protocol definition for Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder.

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial of Linaclotide Administered Orally for 12 Weeks Followed by a 4-Week Randomized Withdrawal Period in Patients With Irritable Bowel Syndrome With Constipation

Conditions
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Irritable Bowel Syndrome Characterized by Constipation

Intervention / Treatment
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* Drug: Linaclotide 290 micrograms
* Drug: Matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient meets protocol criteria for IBS: reports abdominal discomfort or pain that has two or more of the following three features: Relieved with defecation Onset associated with a change in frequency of stool Onset associated with a change in form (appearance) of stool Patient reports < 3 bowel movements (BMs) per week (in the absence of any laxative, suppository, or enema use during the preceding 24 hours) and reports straining, lumpy or hard stools, and/or sensation of incomplete evacuation during > 25% of BMs Patient has successfully completed protocol procedures (with no clinically significant findings): physical exam, 12-lead ECG, or clinical laboratory tests (some patients may require a colonoscopy per American Gastroenterological Association (AGA) guidelines) Patient is compliant with Interactive Voice Response System (IVRS) for daily diary reporting of BM habits and IBS symptoms Exclusion Criteria: Patient has history of loose or watery stools for >25% of BMs Patient has a structural abnormality of the gastrointestinal (GI) tract or a history of a disease or condition that can affect GI motility Patient has any protocol-excluded or clinically significant medical or surgical history or concomitant medication use that 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<br>Linaclotide 290 micrograms | Drug: Linaclotide 290 micrograms<br>* Oral, once daily each morning at least 30 minutes before breakfast for the duration of the study<br>|
| Placebo Comparator: Placebo<br>Matching placebo | Drug: Matching placebo<br>* Oral, once daily each morning at least 30 minutes before breakfast for the duration of the study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 9 Out of 12 Weeks | A patient is considered to be an APC responder if, for at least 9 out of the 12 weeks of the treatment period, the patient had at least 3 CSBMs, experienced an increase of at least 1 CSBM from baseline, and experienced a decrease of at least 30 percent in their Abdominal Pain (AP) score from baseline during a particular week. The AP score assesses the worst of a patient's AP in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no AP and 10 represents very severe AP. A CSBM is defined as a spontaneous bowel movement, associated with a sense of complete evacuation. | Change from Baseline to Week 12 | 
| Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder, 9 Out of 12 Weeks | A patient is considered to be a CSBM 3+1 responder if, for at least 9 out of the 12 weeks of the treatment period, the patient had at least 3 CSBMs and experienced an increase of at least 1 CSBM from baseline during a particular week. A CSBM was defined as a Spontaneous Bowel Movement (SBM) that was associated with a sense of complete evacuation. An SBM was defined as a bowel movement (BM) that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM. | Change from Baseline to Week 12 | 
| Abdominal Pain Responder, 9 Out of 12 Weeks | A patient is considered to be an abdominal pain responder if, for at least 9 out of the 12 weeks of the treatment period, they experienced a decrease of at least 30 percent in the mean abdominal pain score from baseline during a particular week. The Abdominal Pain score assesses the worst of a patient's abdominal pain in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no abdominal pain and 10 represents very severe abdominal pain. | Change from Baseline to Week 12 | 
| Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 6 Out of 12 Weeks. | A patient is considered an APC responder if, for at least 6 of the 12 weeks of the treatment, the patient experienced an increase of at least 1 Complete Spontaneous Bowel Movement (CSBM) from baseline and experienced a decrease of at least 30 percent in their Abdominal Pain (AP)score during a particular week. The AP score assesses the worst of a patient's AP in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no AP and 10 represents very severe AP. A CSBM was defined as a Spontaneous Bowel Movement (SBM) that was associated with a sense of complete evacuation. | Change from Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 12-Week Complete Spontaneous Bowel Movement (CSBM) Frequency Rate | The number of CSBMs per week. | Change from Baseline to Week 12 | 
| 12-Week Spontaneous Bowl Movement (SBM) Frequency Rate | The number of Spontaneous Bowl Movements experienced per week. | Change from Baseline to Week 12 | 
| 12-Week Stool Consistency | The consistency of each BM was assessed by patients using the 7-point Bristol Stool Form Scale (BSFS) from 1 to 7. = 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 stool = watery, no solid pieces [entirely liquid]). | Change from Baseline to Week 12 | 
| 12-Week Severity of Straining | Straining is measured on a 5-point scale where a value of 1 is not at all and a value of 5 is an extreme amount. | Change from Baseline to Week 12 | 
| 12-Week Change in Abdominal Pain Score | Abdominal Pain at its worst (in the last 24 hours) is based on an 11-point scale where 0 represents no abdominal pain and 10 represents very severe abdominal pain. | Change from Baseline to Week 12 | 
| 12-Week Change in Abdominal Discomfort | Abdominal Discomfort is measured on an 11-point scale where a value of 0 is none and a value of 10 is very severe. | Change from Baseline to Week 12 | 
| 12-Week Change in Bloating | Bloating was assessed on an 11-point scale where a value of 0 is none and a value of 10 is very severe. | Change from Baseline to Week 12 | 
| Complete Spontaneous Bowl Movement (CSBM) Responder for 6 Weeks Out of 12 Weeks of Treatment | A patient is considered to be a CSBM responder if, for at least 6 out of the 12 weeks of the treatment period, an increase of at least 1 CSBM per week from baseline was experienced. | Change from Baseline to Week 12 | 
| Abdominal Pain Responder for 6 Out of 12 Weeks | A patient is considered to be an abdominal pain responder if, for at least 6 out of the 12 weeks of the treatment period, they experienced a decrease of 30 percent or more in the abdominal pain score from baseline. The Abdominal Pain score assesses the worst of a patient's abdominal pain in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no abdominal pain and 10 represents very severe abdominal pain. | Change from Baseline to Week 12 | 
| 12-Week Percent of Abdominal Pain-free (APF) Days | Abdominal pain free (APF) days are those days where the patient reported a score of '0' for abdominal pain at its worst Abdominal Pain at its worst (in the last 24 hours) is based on an 11-point scale where 0 represents no abdominal pain and 10 represents very severe abdominal pain. | Change from Baseline to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Irritable Bowel Syndrome, Constipation, Linaclotide