Emricasan, a Caspase Inhibitor, for Treatment of Subjects With Decompensated NASH Cirrhosis (ENCORE-LF)

Study Description

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Brief Summary:

This is a multicenter, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of emricasan in improving event-free survival based on a composite clinical endpoint (where all-cause mortality, new decompensation events, and MELD score progression are events) in subjects with decompensated NASH cirrhosis.

Condition or disease	Intervention/treatment	Phase
Decompensated Cirrhosis	Drug: Emricasan (25 mg); Drug: Emricasan (5 mg); Drug: Placebo	Phase 2

Detailed 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	210 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:	Study drug will be double-blind with matching placebo. Emricasan at 25 mg or 5 mg or matching placebo will be administered orally twice a day.
Primary Purpose:	Treatment
Official Title:	A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, an Oral Caspase Inhibitor, in Subjects With Decompensated Non-Alcoholic Steatohepatitis (NASH) Cirrhosis
Actual Study Start Date :	June 28, 2017
Estimated Primary Completion Date :	August 2019
Estimated Study Completion Date :	August 2019

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Emricasan (25 mg); Emricasan 25 mg	Drug: Emricasan (25 mg); 25 mg emricasan; Other Name: IDN-6556
Active Comparator: Emricasan (5 mg); Emricasan 5mg	Drug: Emricasan (5 mg); 5 mg emricasan; Other Name: IDN-6556
Placebo Comparator: Placebo; Matching placebo	Drug: Placebo; Matching Placebo; Other Name: Matching placebo

Outcome Measures

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Primary Outcome Measures :

1. Comparison of the effect of emricasan on improving event-free survival relative to placebo, based on a composite clinical endpoint [ Time Frame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) ]

Secondary Outcome Measures :

1. Improvement in MELD score [ Time Frame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) ]
   The effect of emricasan on improving MELD score relative to placebo
2. Improvement in Child-Pugh scores [ Time Frame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) ]
   The effect of emricasan on improving the Child-Pugh score relative to placebo
3. Reduction of the proportion of subjects with MELD score progression [ Time Frame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) ]
   The effect of emricasan on reducing the proportion of patients with MELD score progression (≥4 point increase at any study visit) relative to placebo
4. Decrease in new decompensation events [ Time Frame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) ]
   The effect of emricasan on decreasing new decompensation events relative to placebo
5. Decrease in liver transplantation rates [ Time Frame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) ]
   The effect of emricasan on decreasing liver transplantation rates (in association with MELD score ≥25) relative to placebo
6. Decrease in all-cause and liver specific mortality [ Time Frame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) ]
   The effect of emricasan on decreasing all-cause and liver specific mortality relative to placebo
7. Improvement in health-related quality of life (QOL) as measured by Short Form-36 [ Time Frame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) ]
8. 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) ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Key Inclusion Criteria:

1. 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.
2. Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral hepatitis, alcoholic liver disease, etc.)
3. 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.
4. MELD score ≥12 and ≤20 during screening
5. Albumin ≥2.5 g/dL during screening
6. Serum creatinine ≤1.5 mg/dL during screening

Key Exclusion Criteria:

1. Evidence of severe decompensation
2. Non-cirrhotic portal hypertension
3. Child-Pugh score ≥10
4. Current use of anticoagulants that affect prothrombin time or international normalized ratio
5. ALT >3 times upper limit of normal (ULN) or AST >5 times ULN during screening
6. Initiation or discontinuation of non-selective beta blockers within 1 month of screening
7. Transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure within 1 year of screening or previously requiring revision
8. Alpha-fetoprotein >50 ng/mL in the last year
9. History of hepatocellular carcinoma (HCC) or evidence of HCC
10. History of malignancies other than HCC, unless successfully treated with curative intent and believed to be cured
11. Prior liver transplant
12. Uncontrolled diabetes mellitus (HbA1c >9%)
13. Change in diabetes medications or vitamin E within 3 months of screening
14. Restrictive bariatric surgery or bariatric device within 1 year of screening or prior malabsorptive bariatric surgery
15. Symptoms of biliary colic unless resolved following cholecystectomy
16. History of significant alcohol consumption within the past 5 years
17. Current use of medications that are considered inhibitors of organic anion transporting polypeptide OATP1B1 and OATP1B3 transporters
18. Prolongation of screening (pre-treatment) QTcF interval of >500 msecs, or history or presence of clinically concerning cardiac arrhythmias
19. Significant systemic or major illness other than liver disease
20. Human immunodeficiency virus infection
21. 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

Contacts and Locations

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Contacts

Contact: Cathryn Bennett, BN	858-376-2627	cbennett@conatuspharma.com
Contact: Joanne C Imperial, MD, FAASLD		jimperial@conatuspharma.com

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Sponsors and Collaborators

Conatus Pharmaceuticals Inc.

Investigators

Study Director:	Jean L Chan, MD	Conatus Pharmaceuticals

More Information

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Responsible Party:	Conatus Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:	NCT03205345 History of Changes
Other Study ID Numbers:	IDN-6556-17
First Posted:	July 2, 2017
Last Update Posted:	July 24, 2018
Last Verified:	July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Conatus Pharmaceuticals Inc.:

Cirrhosis; NASH Cirrhosis; Decompensated NASH cirrhosis; Cirrhosis, Liver; Non-Alcoholic Fatty Liver Disease

Additional relevant MeSH terms:

Fibrosis; Liver Cirrhosis; Pathologic Processes; Liver Diseases; Digestive System Diseases	Caspase Inhibitors; Cysteine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action