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

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ClinicalTrials.gov Identifier: NCT02686762
Recruitment Status : Completed
First Posted : February 19, 2016
Last Update Posted : August 19, 2019
Sponsor:
Information provided by (Responsible Party):
Conatus Pharmaceuticals Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Non-alcoholic Steatohepatitis Fibrosis Liver Diseases Drug: Emricasan (5 mg) Drug: Emricasan (50 mg) Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 318 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 26, 2016
Actual Primary Completion Date : January 29, 2019
Actual Study Completion Date : February 28, 2019


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 Name: 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 Name: 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.




Primary Outcome Measures :
  1. Fibrosis improvement by at least one stage without worsening of steatohepatitis [ Time Frame: Week 72 ]
    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


Secondary Outcome Measures :
  1. Steatohepatitis resolution (based on liver biopsy) [ Time Frame: Baseline & Week 72 ]
    The proportion of subjects who resolve steatohepatitis without worsening of fibrosis in the emricasan group compared to placebo

  2. Improvement in the Non-alcoholic fatty liver disease (NAFLD) Activity Score [ Time Frame: Baseline & Week 72 ]
    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

  3. Caspase 3/7 Relative Light Units and Alanine aminotransferase (ALT) [ Time Frame: Day 1, week 4, 24, 48, and 72 ]
    To asses whether emricasan compared to placebo improves biomarkers Caspase 3/7 RLU and ALT Unit/Liter (U/L) in subjects with NASH fibrosis.



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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

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02686762


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

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Responsible Party: Conatus Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT02686762     History of Changes
Other Study ID Numbers: IDN-6556-12
First Posted: February 19, 2016    Key Record Dates
Last Update Posted: August 19, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Conatus Pharmaceuticals Inc.:
NASH

Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Fibrosis
Pathologic Processes
Digestive System Diseases
Caspase Inhibitors
Cysteine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action