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

Liver Diseases Clinical Trial

— ENCORE-NF  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02686762
• Other study ID #: IDN-6556-12
• Status: Completed
• Phase: Phase 2
• Start date: January 26, 2016
• Est. completion date: February 28, 2019

Study information

• Verified date: August 2019
• Source: Conatus Pharmaceuticals Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 318
• Est. completion date: February 28, 2019
• Est. primary completion date: January 29, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Fatty Liver
• Fibrosis
• Liver Diseases
• Non-alcoholic Fatty Liver Disease
• Non-alcoholic Steatohepatitis

Intervention

Drug:
• Emricasan (5 mg)
Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (5 mg) twice a day.
• Emricasan (50 mg)
Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (50 mg) twice a day.
• Placebo
Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with a matching placebo twice a day.

Locations

Country	Name	City	State
Germany	Universitätsklinikum der RWTH Aachen	Aachen	North Rhine-Westphalia
Germany	Charité - Universitätsmedizin Berlin	Berlin
Germany	Universitätsklinikum Bonn	Bonning	North Rhine-Westphalia
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	Universitätsklinikum Hamburg Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Eugastro GmbH	Leipzig
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz
Germany	Universitätsklinikum Münster	Munster	North Rhine-Westphalia
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario de La Princesa	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario Puerta de Hierro - Majadahonda	Majadahonda
Spain	Hospital Universitario de Donostia	San Sebastian
Spain	Hospital Universitario Marques de Valdecilla	Santander
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital General Universitario de Valencia	Valencia
United States	Texas Clinical Research Institute	Arlington	Texas
United States	Asheville Gastroenterology Associates, PA	Asheville	North Carolina
United States	Mercy Medical Center	Baltimore	Maryland
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	State University of New York	Buffalo	New York
United States	Lahey Clinic Medical Center	Burlington	Massachusetts
United States	University of Vermont	Burlington	Vermont
United States	Medical University of South Carolina	Charleston	South Carolina
United States	PMG Research at Charleston	Charleston	South Carolina
United States	Carolinas Healthcare System, Center for Liver Disease	Charlotte	North Carolina
United States	ClinSearch, LLC	Chattanooga	Tennessee
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	Consultants for Clinical Research	Cincinnati	Ohio
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	Iowa Digestive Disease Center, P.C	Clive	Iowa
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	iResearch Atlanta LLC	Decatur	Georgia
United States	UnityPoint Clinic Center For Liver Disease	Des Moines	Iowa
United States	Henry Ford Health System	Detroit	Michigan
United States	Duke University Medical Center, Duke South Clinics	Durham	North Carolina
United States	Baylor All Saints Medical Center	Fort Worth	Texas
United States	Fresno Clinical Research Center	Freestone	California
United States	UF Hepatology Research at CTRB	Gainesville	Florida
United States	Gastro One	Germantown	Tennessee
United States	Baylor College of Medicine	Houston	Texas
United States	Liver Associates of Texas, P.A.	Houston	Texas
United States	Research Specialists of Texas	Houston	Texas
United States	Kansas City Research Institute	Kansas City	Missouri
United States	Kansas City VA Medical Center	Kansas City	Missouri
United States	Florida Digestive Health Specialist	Lakewood Ranch	Florida
United States	Preferred Research Partners, Inc.	Little Rock	Arkansas
United States	Pinnacle Clinical Research, PLLC	Live Oak	Texas
United States	Gastrointestinal Biosciences	Los Angeles	California
United States	UCLA The Pfleger Liver Institute	Los Angeles	California
United States	University of Louisville	Louisville	Kentucky
United States	Northwell Health, Inc.	Manhasset	New York
United States	Gastrointestinal Specialists of Georgia	Marietta	Georgia
United States	Methodist University Hospital	Memphis	Tennessee
United States	Miami Veterans Administration Healthcare System	Miami	Florida
United States	University of Miami/Schiff Center for Liver Diseases	Miami	Florida
United States	Vanderbilt University Medical Center - Digestive Disease Center	Nashville	Tennessee
United States	Aquiant Research	New Albany	Indiana
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Columbia University Medical Center (CUMC)	New York	New York
United States	Mount Sinai Beth Israel Medical Center	New York	New York
United States	NYU Langone Medical Center	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Doctors Office Center	Newark	New Jersey
United States	Surinder Singh Saini, M.D., Inc.	Newport Beach	California
United States	Bon Secours Richmond Health System	Newport News	Virginia
United States	Digestive and Liver Disease Specialists	Norfolk	Virginia
United States	Florida Hospital Orlando Transplant Institute	Orlando	Florida
United States	California Liver Research Institute	Pasadena	California
United States	Albert Einstein Medical Center	Philadelphia	Pennsylvania
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	University Gastroenterology	Providence	Rhode Island
United States	Rex Healthcare	Raleigh	North Carolina
United States	Inland Empire Liver Foundation	Rialto	California
United States	McGuire VA Medical Center	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California Davis Medical Center	Sacramento	California
United States	Washington University School of Medicine-Infectious Disease Clinical Research Unit	Saint Louis	Missouri
United States	University of Utah Health Sciences Center	Salt Lake City	Utah
United States	American Research Corporation at the Texas Liver Institue	San Antonio	Texas
United States	Brooke Army Medical Center	San Antonio	Texas
United States	University of California San Diego Medical Center	San Diego	California
United States	University of Washington Harborview Medical Center	Seattle	Washington
United States	Louisiana Research Center, LLC	Shreveport	Louisiana
United States	Tampa General Medical Group	Tampa	Florida
United States	University of Arizona Clinical and Translational Sciences Research Center	Tucson	Arizona
United States	Options Health Research, LLC	Tulsa	Oklahoma
United States	Howard University	Washington	District of Columbia
United States	Sibley Memorial Hospital	Washington	District of Columbia
United States	Cedars Sinai Medical Center	West Hollywood	California

Sponsors (1)

Lead Sponsor	Collaborator
Conatus Pharmaceuticals Inc.

Countries where clinical trial is conducted

United States,  Germany,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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