Companion Protocol for Methacetin Breath Test (MBT) in Conatus Protocol IDN-6556-17

Study Overview
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Brief Summary
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This study is a companion protocol that will use the data generated by Conatus' study of emricasan under protocol IDN-6556-17.The IDN-6556-17 study is a Phase 2, multicenter, double-blind, placebo-controlled trial of Emricasan in subjects with decompensated non-alcoholic steatohepatitis (NASH) cirrhosis.

Detailed Description
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The protocol is intended to validate the ability of the MBT to predict deterioration by 48 weeks for all subjects, and at later time points for those followed longer, for subjects with decompensated NASH cirrhosis in the placebo treatment arm of Conatus' study IDN-6556-17. As one of the Conatus' study secondary objectives, this companion protocol is designed to assess improvement in liver metabolic function as measured by Methacetin Breath Test (MBT) [ Time Frame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) ].

Official Title
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Companion Protocol for the ¹³C-Methacetin Breath Test Using the BreathID® MCS System for Conatus Phase 2 Study of Emricasan, an Oral Caspase Inhibitor, Under Protocol IDN-6556-17

Conditions
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Decompensated Cirrhosis

Intervention / Treatment
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* Combination Product: Methacetin Breath Test
* Drug: Emricasan
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects 18 years or older, able to provide written informed consent and able to understand and willing to comply with the requirements of the study. Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral hepatitis, alcoholic liver disease, etc.) At least one of the following: a) history of variceal hemorrhage (more than 3 months prior to day 1) documented on endoscopy and requiring blood transfusion, b) history of at least moderate ascites (on physical exam or imaging) currently treated with diuretics. MELD score ≥12 and ≤20 during screening Albumin ≥2.5 g/dL during screening Serum creatinine ≤1.5 mg/dL during screening Exclusion Criteria: Evidence of severe decompensation Non-cirrhotic portal hypertension Child-Pugh score ≥10 Current use of anticoagulants that affect prothrombin time or international normalized ratio ALT >3 times upper limit of normal (ULN) or AST >5 times ULN during screening Initiation or discontinuation of non-selective beta blockers within 1 month of screening Transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure within 1 year of screening or previously requiring revision Alpha-fetoprotein >50 ng/mL in the last year History of hepatocellular carcinoma (HCC) or evidence of HCC History of malignancies other than HCC, unless successfully treated with curative intent and believed to be cured Prior liver transplant Uncontrolled diabetes mellitus (HbA1c >9%) Change in diabetes medications or vitamin E within 3 months of screening Restrictive bariatric surgery or bariatric device within 1 year of screening or prior malabsorptive bariatric surgery Symptoms of biliary colic unless resolved following cholecystectomy History of significant alcohol consumption within the past 5 years Current use of medications that are considered inhibitors of organic anion transporting polypeptide OATP1B1 and OATP1B3 transporters Prolongation of screening (pre-treatment) QTcF interval of >500 msecs, or history or presence of clinically concerning cardiac arrhythmias Significant systemic or major illness other than liver disease Human immunodeficiency virus infection Use of alcohol, controlled substances (including inhaled or injected drugs), or non-prescribed use of prescription drugs within 1 year of screening to the point of interfering with the subject's ability to comply with study procedures and study drug administration in the investigator's judgement

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: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study treatment duration will be at least 48 weeks with study visits every 4 weeks up to Week 48 and every 8 weeks after Week 48. All subjects will continue treatment until the last subject in the study reaches 48 weeks in the study. At least 30% of subjects randomized should have baseline MELD score ≥15 and ≤20. For each subject, the study will consist of: Screening period of up to 4 weeks Randomized, double-blind treatment period of at least 48 weeks A follow-up visit 2 weeks after completion of study drug treatment The duration of each subject's participation will be at least 54 weeks for those completing the entire study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Emricasan 25mg<br>The study treatment duration will be at least 48 weeks with study visits every 4 weeks up to Week 48 and every 8 weeks after Week 48. | Combination Product: Methacetin Breath Test<br>* A breath analyzer will be used to measure changes in carbon 12 to carbon13 ratio as a result of metabolism of the Methacetin substrate before and after treatment.<br>Drug: Emricasan<br>* Investigational drug for NASH treatment in Main Conatus protocol<br>|
| Experimental: Emricasan 5mg<br>The study treatment duration will be at least 48 weeks with study visits every 4 weeks up to Week 48 and every 8 weeks after Week 48. | Combination Product: Methacetin Breath Test<br>* A breath analyzer will be used to measure changes in carbon 12 to carbon13 ratio as a result of metabolism of the Methacetin substrate before and after treatment.<br>Drug: Emricasan<br>* Investigational drug for NASH treatment in Main Conatus protocol<br>|
| Placebo Comparator: Placebo<br>The study treatment duration will be at least 48 weeks with study visits every 4 weeks up to Week 48 and every 8 weeks after Week 48. | Combination Product: Methacetin Breath Test<br>* A breath analyzer will be used to measure changes in carbon 12 to carbon13 ratio as a result of metabolism of the Methacetin substrate before and after treatment.<br>Drug: Placebo oral capsule<br>* Placebo versus emricasan in Conatus NASH treatment trial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | Binary diagnosis of subjects that are at high risk to develop a deterioration event as determined by the Methacetin Breath Test (MBT) derived from an algorithm developed under other Exalenz clinical studies using a pre-designed cutoff of Percentage Dose Recovery (PDR) peak of < 5.5%/hour. The data was collected and analyzed agnostic to the intervention. | 1 hour for MBT for assessment of this diagnostic outcome assessed during screening | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | Binary diagnosis of subjects that are at high risk to develop a deterioration event as determined by the Methacetin Breath Test (MBT) derived from an algorithm developed under other Exalenz clinical studies using a pre-designed cutoff of Percentage Dose Recovery (PDR) peak of < 7.5%/hour.The data was collected and analyzed agnostic to the intervention. | 1 hour for MBT for assessment of this diagnostic outcome assessed during screening |