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

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, an Oral Caspase Inhibitor, in Subjects With Decompensated Non-Alcoholic Steatohepatitis (NASH) Cirrhosis

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.

Study Overview

• Status: Unknown
• Conditions: Decompensated Cirrhosis
• Intervention / Treatment: Drug: Placebo; Drug: Emricasan (25 mg); Drug: Emricasan (5 mg)

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 Type: Interventional
• Enrollment (Anticipated): 210
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • The Institute for Liver Health
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital & Medical Center
    • Tucson, Arizona, United States, 85747
      • University Of Arizona Liver Research Institute
  • California
    • Fresno, California, United States, 93701
      • University of California, San Francisco-Fresno
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • Los Angeles, California, United States, 90095
      • UCLA Pfleger Liver Institute
    • Pasadena, California, United States, 91105
      • California Liver Research Institute
    • Redwood City, California, United States, 94063
      • Stanford University
    • Rialto, California, United States, 92377
      • Inland Empire Liver Foundation
    • Sacramento, California, United States, 95817
      • UC Davis GI/Hepatology Clinical Trials Unit
    • San Diego, California, United States, 92037
      • Scripps Clinic - Torrey Pines
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
    • Colorado Springs, Colorado, United States, 80907
      • Peak Enterology Associates
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • West Haven VA Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • UF Hepatology Research at CTRB
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
    • Lakewood Ranch, Florida, United States, 34211
      • Florida Research Institute
    • Miami, Florida, United States, 33136
      • Schiff Center for Liver Disease/University of Miami
    • Orlando, Florida, United States, 32804
      • Florida Hospital Transplant Institute
    • Palmetto Bay, Florida, United States, 33157
      • IMIC Inc.
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Piedmont Transplant Institute
    • Marietta, Georgia, United States, 30060
      • Gastrointestinal Specialists of Georgia
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Indiana
    • Albany, Indiana, United States, 47150
      • Aquiant Research
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics/ Internal Medicine
  • Louisiana
    • Bastrop, Louisiana, United States, 71220
      • Delta Research Partners
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
    • Bethesda, Maryland, United States, 20889
      • Walter Reed National Military Medical Center (WRNMMC)
    • Catonsville, Maryland, United States, 21228
      • Digestive Disease Associates, PA
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Rochester, Minnesota, United States, 55901
      • Mayo Clinic
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center, Division of Digestive Diseases
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • Kansas City Research Institute
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Rutgers New Jersey Medical School
  • New York
    • Manhasset, New York, United States, 11030
      • Northwell Health Inc., Sandra Atlas Bass Center for Liver Diseases.
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
    • New York, New York, United States, 10016
      • NYU Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center - Center for Liver Disease and Transplantation
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Carolinas Healthcare System, Center for Liver Disease
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Morehead City, North Carolina, United States, 28557
      • Diabetes & Endocrinology Consultants, PC
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • UC Health/ UCPC LLC
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Options Health Research, LLC
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Greenville, South Carolina, United States, 29605
      • GHS Gastroenterology and Liver Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • ClinSearch, LLC
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Arlington, Texas, United States, 76012
      • Texas Clinical Research Institute
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75203
      • Methodist Health System Clinical Research Institute
    • Fort Worth, Texas, United States, 76104
      • Baylor Scott & White Research Institute
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine - Advanced Liver Therapies
    • Houston, Texas, United States, 77030
      • Liver Associates of Texas, P.A.
    • San Antonio, Texas, United States, 78234
      • San Antonio Military Medical Center
    • San Antonio, Texas, United States, 78215
      • American Research Corporation at the Texas Liver Institue
    • San Antonio, Texas, United States, 78229
      • Methodist Specialty & Transplant Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Leesburg, Virginia, United States, 20176
      • Emeritas Research Group LLC
    • Newport News, Virginia, United States, 23602
      • Banner University Medical Center - Phoenix Transplant Institute
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
    • Richmond, Virginia, United States, 23226
      • Bon Secours Liver Institute of Virginia
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington
    • Seattle, Washington, United States, 98104
      • University of Washington Harborview Medical Center
    • Seattle, Washington, United States, 98104
      • Swedish Organ Transplant and Liver Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching placebo	Drug: Placebo; Matching Placebo; Other Names: Matching placebo
Active Comparator: Emricasan (25 mg); Emricasan 25 mg	Drug: Emricasan (25 mg); 25 mg emricasan; Other Names: IDN-6556
Active Comparator: Emricasan (5 mg); Emricasan 5mg	Drug: Emricasan (5 mg); 5 mg emricasan; Other Names: IDN-6556

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in MELD score	The effect of emricasan on improving MELD score relative to placebo	Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
Improvement in Child-Pugh scores	The effect of emricasan on improving the Child-Pugh score relative to placebo	Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
Reduction of the proportion of subjects with MELD score progression	The effect of emricasan on reducing the proportion of patients with MELD score progression (≥4 point increase at any study visit) relative to placebo	Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
Decrease in new decompensation events	The effect of emricasan on decreasing new decompensation events relative to placebo	Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
Decrease in liver transplantation rates	The effect of emricasan on decreasing liver transplantation rates (in association with MELD score ≥25) relative to placebo	Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
Decrease in all-cause and liver specific mortality	The effect of emricasan on decreasing all-cause and liver specific mortality relative to placebo	Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
Improvement in health-related quality of life (QOL) as measured by Short Form-36		Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
Improvement in liver metabolic function as measured by Methacetin Breath Test (MBT)		Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)

Collaborators and Investigators

• Sponsor: Conatus Pharmaceuticals Inc.
• Investigators: Study Director: Jean L Chan, MD, Conatus Pharmaceuticals

Publications and helpful links

General Publications

• Frenette C, Kayali Z, Mena E, Mantry PS, Lucas KJ, Neff G, Rodriguez M, Thuluvath PJ, Weinberg E, Bhandari BR, Robinson J, Wedick N, Chan JL, Hagerty DT, Kowdley KV; IDN-6556-17 Study Investigators. Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis. J Hepatol. 2021 Feb;74(2):274-282. doi: 10.1016/j.jhep.2020.09.029. Epub 2020 Oct 8.

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2017
• Primary Completion (Anticipated): August 1, 2019
• Study Completion (Anticipated): August 1, 2019

Study Registration Dates

• First Submitted: June 20, 2017
• First Submitted That Met QC Criteria: June 29, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): March 19, 2019
• Last Update Submitted That Met QC Criteria: March 15, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Cirrhosis; Non-Alcoholic Fatty Liver Disease; Cirrhosis, Liver; NASH Cirrhosis; Decompensated NASH cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis
• Other Study ID Numbers: IDN-6556-17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No