Companion Protocol for Methacetin Breath Test (MBT) in Conatus Protocol IDN-6556-14

Study Overview
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Brief Summary
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To validate the ability of the Methacetin Breath Test (MBT) to detect clinically significant portal hypertension (CSPH)/severe portal hypertension (SPH) defined as hepatic venous pressure gradient (HVPG) ≥ 10 mmHg and HVPG ≥ 12 mmHg respectively, in patients with non-alcoholic steatohepatitis (NASH) during the course of treatment with Conatus's investigational product emricasan/placebo.

Detailed Description
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This study is a companion protocol that will use the data generated by Conatus' study of emricasan under protocol IDN-6556-14 (NCT02960204).The IDN-6556-14 study is a Phase 2, multicenter, double-blind, randomized, placebo-controlled trial in subjects with non-alcoholic steatohepatitis (NASH) cirrhosis and severe portal hypertension. As one of the Conatus' study exploratory objectives, this companion protocol is designed to assess whether emricasan compared to placebo improves liver metabolic function at Weeks 24 and 48 as assessed by the methacetin breath test (at select sites), if relevant.

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-6556-14 (NCT02960204)

Conditions
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NASH - Nonalcoholic Steatohepatitis, Cirrhosis, Portal Hypertension

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.) Compensated cirrhosis OR Decompensated cirrhosis with no more than 1 prior significant decompensating event. Severe portal hypertension defined as HVPG ≥12 mmHg Subjects who are on NSBB, nitrates, diuretics, lactulose, rifaximin, or statins must be on a stable dose for at least 3 months prior to Day 1 Willingness to utilize effective contraception (for both males and females of childbearing potential) from Screening to 4 weeks after the last dose of study drug Exclusion Criteria: Evidence of severe decompensation Severe hepatic impairment defined as a Child-Pugh score ≥10 ALT >3 times upper limit of normal (ULN) or AST >5 times ULN during screening Estimated creatinine clearance <30 mL/min Prior transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure Known portal vein thrombosis Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 months, unless resolved following cholecystectomy, other definitive treatment (e.g. sphincterotomy), or medical management (e.g. ursodeoxycholic acid) Current use of medications that are considered inhibitors of OATP1B1 and OATP1B3 transporters Alpha-fetoprotein >50 ng/mL History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QTcF interval of >500 msec History of or active malignancies, other than those successfully treated with curative intent and believed to be cured Prior liver transplant Change in diabetes medications or vitamin E within 3 months of screening Uncontrolled diabetes mellitus (HbA1c >9%) within 3 months of screening Significant systemic or major illness other than liver disease HIV infection Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of prescription drugs within 1 year of screening If female: planned or known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding Previous treatment with emricasan or active investigational medication (except methacetin) in a clinical trial within 3 months prior to Day 1

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 population performing the MBT at weeks 24 and 48 will have approximately an equal number of subjects from each of the 4 parallel treatment arms (5 mg, 25 mg, 50 mg or placebo).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Emricasan 5mg<br>Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (5 mg) twice a day. The MBT will be performed at screening, at week 24/week 48/at early termination. | Combination Product: Methacetin Breath Test<br>* A breath analyzer will be used to measure changes in carbon-12 to carbon-13 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 25mg<br>Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (25 mg) twice a day. The MBT will be performed at screening, at week 24/ week 48/ at early termination. | Combination Product: Methacetin Breath Test<br>* A breath analyzer will be used to measure changes in carbon-12 to carbon-13 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 50mg<br>Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (50 mg) twice a day. The MBT will be performed at screening, at week 24/ week 48/ at early termination. | Combination Product: Methacetin Breath Test<br>* A breath analyzer will be used to measure changes in carbon-12 to carbon-13 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>Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with a matching placebo twice a day. The MBT will be performed at screening, at week 24/week 48/at early termination. | Combination Product: Methacetin Breath Test<br>* A breath analyzer will be used to measure changes in carbon-12 to carbon-13 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 With Matched Clinically Significant Portal Hypertension Based on Hepatic Venous Pressure Gradient (HVPG) and Methacetin Breath Test (MBT) | Binary diagnosis of clinically significant portal hypertension (CSPH) as determined by HVPG, defined as HVPG ≥ 10mmHg and by the MBT derived from an algorithm developed under other Exalenz clinical studies | 1 hour for MBT related to assessment of this diagnostic primary outcome assesses during screening | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Matched Subjects With Significant Portal Hypertension (Defined as HVPG>=12mmHg) Based on HVPG and MBT | Binary diagnosis of HVPG>=12mmHg and by the MBT derived from an algorithm developed under other Exalenz clinical studies | 1 hour for MBT for assessment of this diagnostic secondary outcome assessed during screening |