Clinical trial NCT02686762: Emricasan, a Caspase Inhibitor, for Evaluation in Subjects With Non-Alcoholic Steatohepatitis (NASH) Fibrosis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-alcoholic Steatohepatitis
Fibrosis
Liver Diseases
Keywords: NASH
Lead sponsor: Conatus Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2016-02-19
Enrollment: 318
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Fibrosis improvement by at least one stage without worsening of steatohepatitis
timeFrame: Week 72
Secondary outcomes:
measure: Steatohepatitis resolution (based on liver biopsy)
timeFrame: Baseline & Week 72
measure: Improvement in the Non-alcoholic fatty liver disease (NAFLD) Activity Score
timeFrame: Baseline & Week 72
measure: Caspase 3/7 Relative Light Units and Alanine aminotransferase (ALT)
timeFrame: Day 1, week 4, 24, 48, and 72
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Tucson
country: United States
facility: University of Arizona Clinical and Translational Sciences Research Center
state: Arizona
city: Little Rock
country: United States
facility: Preferred Research Partners, Inc.
state: Arkansas
city: Freestone
country: United States
facility: Fresno Clinical Research Center
state: California
city: Los Angeles
country: United States
facility: UCLA The Pfleger Liver Institute
state: California
city: Los Angeles
country: United States
facility: Gastrointestinal Biosciences
state: California
city: Newport Beach
country: United States
facility: Surinder Singh Saini, M.D., Inc.
state: California
city: Pasadena
country: United States
facility: California Liver Research Institute
state: California
city: Rialto
country: United States
facility: Inland Empire Liver Foundation
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: San Diego
country: United States
facility: University of California San Diego Medical Center
state: California
city: West Hollywood
country: United States
facility: Cedars Sinai Medical Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Washington
country: United States
facility: Sibley Memorial Hospital
state: District of Columbia
city: Washington
country: United States
facility: Howard University
state: District of Columbia
city: Gainesville
country: United States
facility: UF Hepatology Research at CTRB
state: Florida
city: Lakewood Ranch
country: United States
facility: Florida Digestive Health Specialist
state: Florida
city: Miami
country: United States
facility: Miami Veterans Administration Healthcare System
state: Florida
city: Miami
country: United States
facility: University of Miami/Schiff Center for Liver Diseases
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Orlando Transplant Institute
state: Florida
city: Tampa
country: United States
facility: Tampa General Medical Group
state: Florida
city: Decatur
country: United States
facility: iResearch Atlanta LLC
state: Georgia
city: Marietta
country: United States
facility: Gastrointestinal Specialists of Georgia
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: New Albany
country: United States
facility: Aquiant Research
state: Indiana
city: Clive
country: United States
facility: Iowa Digestive Disease Center, P.C
state: Iowa
city: Des Moines
country: United States
facility: UnityPoint Clinic Center For Liver Disease
state: Iowa
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Shreveport
country: United States
facility: Louisiana Research Center, LLC
state: Louisiana
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Clinic Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: Kansas City VA Medical Center
state: Missouri
city: Kansas City
country: United States
facility: Kansas City Research Institute
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine-Infectious Disease Clinical Research Unit
state: Missouri
city: Newark
country: United States
facility: Doctors Office Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Buffalo
country: United States
facility: State University of New York
state: New York
city: Manhasset
country: United States
facility: Northwell Health, Inc.
state: New York
city: New York
country: United States
facility: Mount Sinai Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center (CUMC)
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Asheville
country: United States
facility: Asheville Gastroenterology Associates, PA
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Healthcare System, Center for Liver Disease
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center, Duke South Clinics
state: North Carolina
city: Raleigh
country: United States
facility: Rex Healthcare
state: North Carolina
city: Cincinnati
country: United States
facility: Consultants for Clinical Research
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Tulsa
country: United States
facility: Options Health Research, LLC
state: Oklahoma
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Medical Center
state: Pennsylvania
city: Providence
country: United States
facility: University Gastroenterology
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Charleston
country: United States
facility: PMG Research at Charleston
state: South Carolina
city: Chattanooga
country: United States
facility: ClinSearch, LLC
state: Tennessee
city: Germantown
country: United States
facility: Gastro One
state: Tennessee
city: Memphis
country: United States
facility: Methodist University Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center - Digestive Disease Center
state: Tennessee
city: Arlington
country: United States
facility: Texas Clinical Research Institute
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Baylor All Saints Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: Liver Associates of Texas, P.A.
state: Texas
city: Houston
country: United States
facility: Research Specialists of Texas
state: Texas
city: Live Oak
country: United States
facility: Pinnacle Clinical Research, PLLC
state: Texas
city: San Antonio
country: United States
facility: American Research Corporation at the Texas Liver Institue
state: Texas
city: San Antonio
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Burlington
country: United States
facility: University of Vermont
state: Vermont
city: Newport News
country: United States
facility: Bon Secours Richmond Health System
state: Virginia
city: Norfolk
country: United States
facility: Digestive and Liver Disease Specialists
state: Virginia
city: Richmond
country: United States
facility: McGuire VA Medical Center
state: Virginia
city: Seattle
country: United States
facility: University of Washington Harborview Medical Center
state: Washington
city: Aachen
country: Germany
facility: Universitätsklinikum der RWTH Aachen
state: North Rhine-Westphalia
city: Bonning
country: Germany
facility: Universitätsklinikum Bonn
state: North Rhine-Westphalia
city: Munster
country: Germany
facility: Universitätsklinikum Münster
state: North Rhine-Westphalia
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Leipzig
country: Germany
facility: Eugastro GmbH
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro - Majadahonda
city: San Sebastian
country: Spain
facility: Hospital Universitario de Donostia
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
Study officials:
affiliation: Conatus Pharmaceuticals Inc.
name: Jean L Chan, MD
role: STUDY_CHAIR
References:
citation: 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.