A Phase 3, International, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety Trial of Linaclotide Administered Orally for 12 Weeks to Patients With Irritable Bowel Syndrome With Constipation (IBS-C)

Study Overview
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Brief Summary
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This clinical trial is an international, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial comparing one dose of linaclotide to placebo. Approximately 800 patients with a diagnosis of IBS-C (modified Rome III criteria) will be randomized at up to 60 trial centers in China, Australia, and New Zealand. The trial will consist of up to 21 days of screening, 14 to 21 days of pre-treatment, 12 weeks of double-blind treatment, and 2 weeks of follow-up. At the end of the Pre-treatment Period, patients meeting the entry criteria for this trial will be randomized to one of two double-blind treatment groups: 290 ug linaclotide, or placebo (1:1).

Official Title
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A Phase 3, International, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety Trial of Linaclotide Administered Orally for 12 Weeks to Patients With Irritable Bowel Syndrome With Constipation (IBS-C)

Conditions
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Irritable Bowel Syndrome With Constipation (IBS-C)

Intervention / Treatment
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* Drug: Placebo
* Drug: Linaclotide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has signed an Informed Consent Form(ICF). Patient Must not be pregnant or breastfeeding and agree to use birth control Patient meets the colonoscopy requirements defined by the American Gastroenterological Association guidelines and no clinically-significant laboratory or physical examination findings; Patient meets protocol-defined criteria for Irritable Bowel Syndrome with Constipation(IBS-C), including stool frequency, straining, stool consistency, abdominal pain, and abdominal discomfort criteria Patient meets protocol-defined eDiary completion Compliance and agrees to refrain from making any new, major life-style changes that may affect IBS-C symptoms Exclusion Criteria: Recent history of mushy or watery stools Various medical conditions, medical histories, or family medical histories that would not make the patient a good candidate for the study Patient currently has both unexplained and clinically significant alarm symptoms or systemic signs of infection or colitis. Surgery to the gastrointestinal tract Usage of prohibited medications

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: controlled arm<br> | Drug: Placebo<br>* matching Placebo Capsules, Oral, once daily<br>|
| Experimental: treatment arm<br> | Drug: Linaclotide<br>* Linaclotide 290 ug Capsules, Oral, once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 12-week Abdominal Pain/Abdominal Discomfort Weekly Responder | A 12-week Abdominal Pain/Abdominal Discomfort Responder is a patient who meets the Abdominal Pain/Abdominal Discomfort Weekly Responder criteria (i.e., an improvement of ≥30% from baseline in either the mean abdominal pain score or mean abdominal discomfort score for that week, with neither score worsening from baseline for that week) for at least 6 out of the 12 weeks of the Treatment Period. Abdominal pain at its worst (in the last 24 hours) was assessed daily by patients on an 11-point numerical rating scale (NRS) where 0 represents no abdominal pain and 10 represents very severe abdominal pain. Abdominal discomfort (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal discomfort and 10 represents very severe abdominal discomfort. | Baseline and Weeks 1-12 during the Treatment Period | 
| 12-week Irritable Bowel Syndrome (IBS) Degree of Relief Responder | A 12-week IBS Degree of Relief Responder is a patient who meets the IBS Degree of Relief Weekly Responder criteria (i.e., response to the degree of relief of IBS symptoms question for that week was Considerably relieved or Completely relieved) for at least 6 out of the 12 weeks of the Treatment Period. Degree of relief of IBS symptoms (in the last 7 days) was assessed weekly by patients on a 7-point balanced ordinal scale where 1 = Completely relieved, 4 = Unchanged, and 7 = As bad as I can imagine. | Baseline and Weeks 1-12 during the Treatment Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 12-week Complete Spontaneous Bowel Movement Frequency Rate | The change from baseline in 12-week CSBM frequency (i.e., average weekly CSBM frequency over the 12 weeks of the Treatment Period). A spontaneous bowel movement (SBM) is defined as a bowel movement without laxative use in the preceding 24 hours. A CSBM is defined as an SBM that is associated with a sense of complete evacuation. | Baseline and 12-week Treatment Period | 
| Change From Baseline in 12-week Spontaneous Bowel Movement Frequency Rate | The change from baseline in 12-week SBM frequency (i.e., average weekly SBM frequency over the 12 weeks of the Treatment Period). SBM is defined as a bowel movement without laxative use in the preceding 24 hours. | Baseline and 12-week Treatment Period | 
| Change From Baseline in 12-week Stool Consistency | The change from baseline in 12-week stool consistency (i.e., the average of the non-missing Bristol Stool Form Scale [BSFS] score from the SBMs occurring during the 12-week Treatment Period). Consistency of each bowel movement was assessed daily by patients using the 7-point BSFS (1=Separate hard lumps like nuts [difficult to pass] to 7=Watery, no solid pieces [entirely liquid]). | Baseline and 12-week Treatment Period | 
| Change From Baseline in 12-week Severity of Straining | The change from baseline in 12-week severity of straining (i.e., the average of the non-missing straining scores from the SBMs occurring during the 12-week Treatment Period). Severity of straining was assessed daily by patients on a 5-point ordinal scale (1=Not at all to 5=An extreme amount). | Baseline and 12-week Treatment Period | 
| Change From Baseline in 12-week Abdominal Bloating | The change from baseline in 12-week abdominal bloating (i.e., the average of the non-missing daily abdominal bloating scores reported during the 12-week Treatment Period). Abdominal bloating (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal bloating and 10 represents very severe abdominal bloating. | Baseline and 12-week Treatment Period | 
| Change From Baseline in 12-week Abdominal Pain | The change from baseline in 12-week abdominal pain (i.e., the average of the non-missing daily abdominal pain scores reported during the 12-week Treatment Period). Abdominal pain at its worst (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal pain and 10 represents very severe abdominal pain. | Baseline and 12-week Treatment Period | 
| Change From Baseline in 12-week Abdominal Discomfort | The change from baseline in 12-week abdominal discomfort (i.e., the average of the non-missing daily abdominal discomfort scores reported during the 12-week Treatment Period). Abdominal discomfort (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal discomfort and 10 represents very severe abdominal discomfort. | Baseline and 12-week Treatment Period |