A 12-Week Study With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Tenapanor for the Treatment of IBS-C

Study Overview
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Brief Summary
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This phase 3, 12-week, randomized, double-blind, placebo-controlled, multi-center study will evaluate the safety and efficacy of tenapanor in subjects with constipation-predominant irritable bowel syndrome (IBS-C) as defined by the ROME III criteria and who have active disease as determined after a two-week screening period. Subjects who qualify and are randomized into the study will either receive 50mg BID of tenapanor or placebo BID for 12 week treatment period and then undergo a 4 week placebo controlled randomized withdrawal.

Detailed Description
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During the 12-week treatment period, subjects will record daily assessments including: frequency and timing of bowel movements; sensation and complete bowel emptying; consistency of bowel movements; degree of straining, worst abdominal pain, abdominal discomfort, abdominal bloating, abdominal fullness and abdominal cramping. Subjects will also record weekly assessments including: adequate relief of IBS severity, and constipation severity. At the end of the 12-week treatment period, there will be a 4-week randomized withdrawal period in which subjects who complete the study in Tenapanor group will be randomized to either Tenapanor 50mg BID or placebo BID (1:1) and subjects who complete the study in the placebo group will be assigned to receive Tenapanor 50mg BID.

Official Title
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A 12-Week, Randomized, Double-Blind, Placebo-Controlled Study With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Tenapanor for the Treatment of Constipation-Predominant Irritable Bowel Syndrome (IBS-C)

Conditions
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Constipation Predominant Irritable Bowel Syndrome

Intervention / Treatment
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* Drug: Tenapanor
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 75 years old Females must be of non-childbearing potential; If of child-bearing potential, must have negative pregnancy test and confirm the use of one of the appropriate means of contraception. Males must agree to use an appropriate method of barrier contraception or have documented surgical sterilization Subject meets definition of IBS-C using Rome III Criteria for the Diagnosis of IBS A colonoscopy based on AGA guidelines; every 10 years at ≥ 50 years old, or the occurrence of any warning signs Exclusion Criteria: Functional diarrhea as defined by Rome III criteria IBS with diarrhea (IBS-D), mixed IBS (IBS-M), or unsubtyped IBS as defined by Rome III criteria Diagnosis or treatment of any clinically symptomatic biochemical or structural abnormality of the GI tract within 6 months prior to screening, or active disease within 6 months prior to screening; including but not limited to cancer, inflammatory bowel disease, diverticulitis, duodenal ulcer, erosive esophagitis, gastric ulcer, pancreatitis (within 12 months of screening), cholelithiasis, amyloidosis, ileus, non-controlled GERD, gastrointestinal obstruction, ischemic colitis or carcinoid syndrome. Subject has a history or current evidence of laxative abuse (in the clinical judgment of the physician) Hepatic dysfunction (ALT [SGPT] or AST [SGOT] >2.5 times the upper limit of normal) or renal impairment (serum creatinine > 2mg/dL) Any evidence of or treatment of malignancy (other than localized basal cell, squamous cell skin cancer or cancer in situ that has been resected) within the previous year Any surgery on the stomach, small intestine or colon, excluding appendectomy or cholecystectomy (unless within 60 days of screening visit)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: 50mg BID<br>Tenapanor | Drug: Tenapanor<br> <br> * Other names: AZD1722;|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 of 12 Week Overall Responder Rate | An overall responder is defined as a weekly responder for the first 6/12 weeks where both CSBM and abdominal pain response criteria were met for the week. The CSBM response criteria are defined as an increase of one or more change in average weekly CSBMs from baseline. The definition of a CSBM is as follows: A CSBM is a spontaneous bowel movement (SBM) for which the subject responds yes to the following question; Did you feel like you completely emptied your bowels? The abdominal pain response criterion is defined as a decrease of 30% or more of percent change in average weekly worst abdominal pain from baseline. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 of 12 Week Overall Complete Spontaneous Bowel Movement (CSBM)Responder Rate | An overall CSBM responder is defined as a weekly responder for the first 6/12 weeks. The CSBM response criteria are defined as an increase of one or more change in average weekly CSBMs from baseline. The definition of a CSBM is as follows: A CSBM is a spontaneous bowel movement (SBM) for which the subject responds yes to the following question; Did you feel like you completely emptied your bowels? | 12 weeks | 
| 6 of 12 Week Overall Abdominal Pain Responder Rate | An overall abdominal pain responder is defined as a weekly responder for the first 6/12. The abdominal pain response criterion is defined as a decrease of 30% or more of percent change in average weekly worst abdominal pain from baseline. | 12 weeks | 
| 9 of 12 Week Overall Responder Rate | An overall responder is defined as a weekly responder for the first 9/12 weeks where both CSBM and abdominal pain response criteria were met for the week. The CSBM response criteria are defined as an increase of one or more change in average weekly CSBMs from baseline and a minimum of at least 3 CSBMs that same week. The definition of a CSBM is as follows: A CSBM is a spontaneous bowel movement (SBM) for which the subject responds yes to the following question; Did you feel like you completely emptied your bowels? The abdominal pain response criterion is defined as a decrease of 30% or more of percent change in average weekly worst abdominal pain from baseline. | 12 weeks | 
| 9 of 12 Week Overall CSBM Responder Rate | An overall CSBM responder is defined as a weekly responder for the first 9/12 weeks. The CSBM response criteria are defined as an increase of one or more change in average weekly CSBMs from baseline and a minimum of at least 3 CSBMs that same week. The definition of a CSBM is as follows: A CSBM is a spontaneous bowel movement (SBM) for which the subject responds yes to the following question; Did you feel like you completely emptied your bowels? | 12 weeks | 
| 9 of 12 Week Overall Abdominal Pain Responder Rate | An overall abdominal pain responder is defined as a weekly responder for the first 9/12 weeks. The abdominal pain response criterion is defined as a decrease of 30% or more of percent change in average weekly worst abdominal pain from baseline. | 12 weeks |