Emricasan, a Caspase Inhibitor, for Evaluation in Subjects With Non-Alcoholic Steatohepatitis (NASH) Fibrosis (ENCORE-NF)

A Multicenter, Randomized, Double-Blind, Placebo-controlled Trial of Emricasan (IDN-6556-12), an Oral Caspase Inhibitor, in Subjects With Non-alcoholic Steatohepatitis (NASH) Fibrosis

This is a multicenter, double-blind, randomized, placebo-controlled trial involving subjects with a diagnosis of "definite NASH" with fibrosis (excluding cirrhosis) as determined by the central histopathologist. Upon successful screening, subjects will be randomized to receive either emricasan 50 mg BID or emricasan 5 mg BID or matching placebo BID.

Study Overview

• Status: Completed
• Conditions: Liver Diseases; Fibrosis; Non-alcoholic Steatohepatitis
• Intervention / Treatment: Drug: Emricasan (5 mg); Drug: Emricasan (50 mg); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 318
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Charité - Universitätsmedizin Berlin
  • Freiburg, Germany, 79106
    • Universitätsklinikum Freiburg
  • Hamburg, Germany, 20246
    • Universitatsklinikum Hamburg Eppendorf
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Leipzig, Germany, 04103
    • Eugastro GmbH
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
  • North Rhine-Westphalia
    • Aachen, North Rhine-Westphalia, Germany, 52074
      • Universitätsklinikum der RWTH Aachen
    • Bonning, North Rhine-Westphalia, Germany, 53127
      • Universitätsklinikum Bonn
    • Munster, North Rhine-Westphalia, Germany, 48149
      • Universitätsklinikum Münster
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28006
    • Hospital Universitario De La Princesa
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañón
  • Majadahonda, Spain, 28222
    • Hospital Universitario Puerta de Hierro - Majadahonda
  • San Sebastian, Spain, 20014
    • Hospital Universitario de Donostia
  • Santander, Spain, 39008
    • Hospital Universitario Marques de Valdecilla
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
  • Valencia, Spain, 46104
    • Hospital General Universitario de Valencia
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Clinical and Translational Sciences Research Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Preferred Research Partners, Inc.
  • California
    • Freestone, California, United States, 93701
      • Fresno Clinical Research Center
    • Los Angeles, California, United States, 90067
      • GastroIntestinal BioSciences
    • Los Angeles, California, United States, 90024
      • UCLA The Pfleger Liver Institute
    • Newport Beach, California, United States, 92660
      • Surinder Singh Saini, M.D., Inc.
    • Pasadena, California, United States, 91105
      • California Liver Research Institute
    • Rialto, California, United States, 92377
      • Inland Empire Liver Foundation
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • San Diego, California, United States, 92103
      • University of California San Diego Medical Center
    • West Hollywood, California, United States, 90048
      • Cedars Sinai Medical Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20016
      • Sibley Memorial Hospital
    • Washington, District of Columbia, United States, 20059
      • Howard University
  • Florida
    • Gainesville, Florida, United States, 32610
      • UF Hepatology Research at CTRB
    • Lakewood Ranch, Florida, United States, 34211
      • Florida Digestive Health Specialist
    • Miami, Florida, United States, 33125
      • Miami Veterans Administration HealthCare System
    • Miami, Florida, United States, 33136
      • University of Miami/Schiff Center for Liver Diseases
    • Orlando, Florida, United States, 32804
      • Florida Hospital Orlando Transplant Institute
    • Tampa, Florida, United States, 33606
      • Tampa General Medical Group
  • Georgia
    • Decatur, Georgia, United States, 30030
      • iResearch Atlanta LLC
    • Marietta, Georgia, United States, 30060
      • Gastrointestinal Specialists of Georgia
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Medical Center
  • Indiana
    • New Albany, Indiana, United States, 47150
      • Aquiant Research
  • Iowa
    • Clive, Iowa, United States, 50325
      • Iowa Digestive Disease Center, P.C
    • Des Moines, Iowa, United States, 50309
      • UnityPoint Clinic Center For Liver Disease
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
    • Shreveport, Louisiana, United States, 71105
      • Louisiana Research Center, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
    • Bethesda, Maryland, United States, 20889
      • Walter Reed National Military Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Burlington, Massachusetts, United States, 01803
      • Lahey Clinic Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • Kansas City Research Institute
    • Kansas City, Missouri, United States, 64128
      • Kansas City VA Medical Center
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine-Infectious Disease Clinical Research Unit
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Doctors Office Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Buffalo, New York, United States, 14203
      • State University of New York
    • Manhasset, New York, United States, 11030
      • Northwell Health, Inc.
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center (CUMC)
    • New York, New York, United States, 10003
      • Mount Sinai Beth Israel Medical Center
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Asheville Gastroenterology Associates, PA
    • Charlotte, North Carolina, United States, 28204
      • Carolinas Healthcare System, Center for Liver Disease
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center, Duke South Clinics
    • Raleigh, North Carolina, United States, 27607
      • Rex Healthcare
  • Ohio
    • Cincinnati, Ohio, United States, 45249
      • Consultants for Clinical Research
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Options Health Research, LLC
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • University Gastroenterology
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Charleston, South Carolina, United States, 29461
      • PMG Research at Charleston
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • ClinSearch, LLC
    • Germantown, Tennessee, United States, 38138
      • Gastro One
    • Memphis, Tennessee, United States, 38104
      • Methodist University Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center - Digestive Disease Center
  • Texas
    • Arlington, Texas, United States, 76012
      • Texas Clinical Research Institute
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Fort Worth, Texas, United States, 76104
      • Baylor All Saints Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • Research Specialists of Texas
    • Houston, Texas, United States, 77030
      • Liver Associates of Texas, P.A.
    • Live Oak, Texas, United States, 78233
      • Pinnacle Clinical Research, PLLC
    • San Antonio, Texas, United States, 78219
      • Brooke Army Medical Center
    • San Antonio, Texas, United States, 78215
      • American Research Corporation at the Texas Liver Institue
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health Sciences Center
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont
  • Virginia
    • Newport News, Virginia, United States, 23602
      • Bon Secours Richmond Health System
    • Norfolk, Virginia, United States, 23502
      • Digestive and Liver Disease Specialists
    • Richmond, Virginia, United States, 23249
      • McGuire VA Medical Center
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington Harborview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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. Histological evidence of definite NASH based on NASH CLinical Research Network (CRN) criteria, as confirmed by the central histopathologist, on a liver biopsy obtained no more than 6 months prior to Day 1
3. NAFLD Activity Score (NAS) of 4 or greater with a score of at least 1 in each component of the NAS (steatosis scored 0-3, lobular inflammation scored 0-3, ballooning scored 0-2)

4. Fibrosis stage 1 (limited to 20% of subjects), stage 2, or stage 3 using the NASH CRN Histologic Scoring System

   a. Subjects with fibrosis stage 1 must also have diabetes mellitus or metabolic syndrome

5. 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
6. If on vitamin E or pioglitazone, subjects must have been on a stable dose for at least 3 months prior to the biopsy (whether historical or qualifying biopsy)

Exclusion Criteria:

1. Current or history of significant alcohol consumption, defined as more than 20 g/day for females and more than 30 g/day in males on average, or inability to reliably quantify alcohol consumption based on investigator's judgement
2. Use of the following drugs (which may have potential hepatotoxic effects) within 6 months prior to Day 1: amiodarone, methotrexate, tamoxifen, valproic acid, estrogens at doses greater than those used for hormone replacement or contraception, anabolic steroids, or systemic glucocorticoids for more than 4 weeks at doses greater than replacement doses
3. Uncontrolled diabetes (HbA1c ≥9%) within 60 days prior to Day 1
4. Presence of cirrhosis on liver biopsy (fibrosis stage 4 based on the central histopathologist reading)

5. Hepatitis and fibrosis more likely related to etiologies other than NASH such as:

   1. alcoholic steatohepatitis
   2. autoimmune hepatitis
   3. hepatitis B virus (HBV) infection
   4. hepatitis C virus (HCV) infection
   5. primary biliary cirrhosis
   6. primary sclerosing cholangitis
   7. Wilson's disease
   8. alpha-1-antitrypsin deficiency
   9. hemochromatosis or iron overload
   10. drug-induced liver disease
   11. other biliary liver disease
6. ALT or AST >5 times upper limit of normal (ULN) or total bilirubin >1.5 times ULN during screening (unless subject has elevated total bilirubin due to Gilbert's as documented in the medical records)
7. Alpha-fetoprotein >200 ng/mL
8. Hemoglobin <10 g/dL
9. White blood cell count <2.0 x 10^3/mm3
10. Estimated creatinine clearance <30 mL/min
11. Current use of the following medications that are considered significant inhibitors of OATP1B1 and OATP1B3 transporters: atazanavir, cyclosporine, eltrombopag, gemfibrozil, indinavir, lopinavir, ritonavir, rifampin, saquinavir, simeprevir, telaprevir, tipranovir, or some combination of these medications
12. Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 months, unless resolved following cholecystectomy
13. Inability to safely obtain a liver biopsy
14. Known human immunodeficiency virus (HIV) infection
15. Weight loss ≥ 10% within 6 months of Day 1
16. Use of 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
17. History of or active malignancies, other than those successfully treated with curative intent and believed to be cured
18. Significant systemic or major illness other than liver disease that in the opinion of the investigator would preclude the subject from participating in and completing the study, including but not limited to acute coronary syndrome or stroke within 6 months of screening or major surgery within 3 months of screening
19. History or presence of clinically concerning cardiac arrhythmias, or prolongation of Screening (pre-treatment) QTcF interval >480 milliseconds (msec)
20. Prior or planned (during the time frame of the study) bariatric surgery
21. If female: planned or known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding
22. Previous treatment with emricasan or active investigational medication in a clinical trial within 6 months prior to Day 1
23. Prior liver transplant

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
Active Comparator: Emricasan (5 mg); Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (5 mg) twice a day.	Drug: Emricasan (5 mg); Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (5 mg) twice a day.; Other Names: IDN-6556
Active Comparator: Emricasan (50 mg); Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (50 mg) twice a day.	Drug: Emricasan (50 mg); Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (50 mg) twice a day.; Other Names: IDN-6556
Placebo Comparator: Matching Placebo; Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with a matching placebo twice a day.	Drug: Placebo; Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with a matching placebo twice a day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fibrosis improvement by at least one stage without worsening of steatohepatitis	Proportion of subjects who improve fibrosis on liver biopsy by at least one stage without worsening of steatohepatitis in the emricasan group compared to placebo	Week 72

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Steatohepatitis resolution (based on liver biopsy)	The proportion of subjects who resolve steatohepatitis without worsening of fibrosis in the emricasan group compared to placebo	Baseline & Week 72
Improvement in the Non-alcoholic fatty liver disease (NAFLD) Activity Score	The proportion of subjects who improve the NAFLD Activity Score (NAS), its components (steatosis, lobular inflammation, ballooning), and portal inflammation, in the emricasan group compared to placebo	Baseline & Week 72
Caspase 3/7 Relative Light Units and Alanine aminotransferase (ALT)	To asses whether emricasan compared to placebo improves biomarkers Caspase 3/7 RLU and ALT Unit/Liter (U/L) in subjects with NASH fibrosis.	Day 1, week 4, 24, 48, and 72

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Harrison SA, Goodman Z, Jabbar A, Vemulapalli R, Younes ZH, Freilich B, Sheikh MY, Schattenberg JM, Kayali Z, Zivony A, Sheikh A, Garcia-Samaniego J, Satapathy SK, Therapondos G, Mena E, Schuppan D, Robinson J, Chan JL, Hagerty DT, Sanyal AJ. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J Hepatol. 2020 May;72(5):816-827. doi: 10.1016/j.jhep.2019.11.024. Epub 2019 Dec 27.

Study record dates

Study Major Dates

• Study Start (Actual): January 26, 2016
• Primary Completion (Actual): January 29, 2019
• Study Completion (Actual): February 28, 2019

Study Registration Dates

• First Submitted: February 10, 2016
• First Submitted That Met QC Criteria: February 16, 2016
• First Posted (Estimate): February 19, 2016

Study Record Updates

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

More Information

Terms related to this study

• Keywords: NASH
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: IDN-6556-12

Plan for Individual participant data (IPD)

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