Emricasan, a Caspase Inhibitor, for Treatment of Subjects With Decompensated NASH Cirrhosis

Decompensated Cirrhosis Clinical Trial

— ENCORE-LF  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03205345
• Other study ID #: IDN-6556-17
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 28, 2017
• Est. completion date: August 2019

Study information

• Verified date: March 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 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 210
• Est. completion date: August 2019
• Est. primary completion date: August 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Decompensated Cirrhosis
• Fibrosis
• Liver Cirrhosis

Intervention

Drug:
• Emricasan (25 mg)
25 mg emricasan
• Emricasan (5 mg)
5 mg emricasan
• Placebo
Matching Placebo

Locations

Country	Name	City	State
United States	Aquiant Research	Albany	Indiana
United States	Texas Clinical Research Institute	Arlington	Texas
United States	Piedmont Transplant Institute	Atlanta	Georgia
United States	University of Colorado Denver	Aurora	Colorado
United States	Mercy Medical Center	Baltimore	Maryland
United States	Delta Research Partners	Bastrop	Louisiana
United States	Walter Reed National Military Medical Center (WRNMMC)	Bethesda	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Digestive Disease Associates, PA	Catonsville	Maryland
United States	The Institute for Liver Health	Chandler	Arizona
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Healthcare System, Center for Liver Disease	Charlotte	North Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	ClinSearch, LLC	Chattanooga	Tennessee
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	UC Health/ UCPC LLC	Cincinnati	Ohio
United States	Peak Enterology Associates	Colorado Springs	Colorado
United States	Methodist Health System Clinical Research Institute	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Baylor Scott & White Research Institute	Fort Worth	Texas
United States	University of California, San Francisco-Fresno	Fresno	California
United States	UF Hepatology Research at CTRB	Gainesville	Florida
United States	GHS Gastroenterology and Liver Center	Greenville	South Carolina
United States	Baylor College of Medicine - Advanced Liver Therapies	Houston	Texas
United States	Liver Associates of Texas, P.A.	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics/ Internal Medicine	Iowa City	Iowa
United States	University of Mississippi Medical Center, Division of Digestive Diseases	Jackson	Mississippi
United States	Mayo Clinic	Jacksonville	Florida
United States	Kansas City Research Institute	Kansas City	Missouri
United States	Florida Research Institute	Lakewood Ranch	Florida
United States	Emeritas Research Group LLC	Leesburg	Virginia
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	UCLA Pfleger Liver Institute	Los Angeles	California
United States	Northwell Health Inc., Sandra Atlas Bass Center for Liver Diseases.	Manhasset	New York
United States	Gastrointestinal Specialists of Georgia	Marietta	Georgia
United States	Schiff Center for Liver Disease/University of Miami	Miami	Florida
United States	Diabetes & Endocrinology Consultants, PC	Morehead City	North Carolina
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Columbia University Medical Center - Center for Liver Disease and Transplantation	New York	New York
United States	NYU Medical Center	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Rutgers New Jersey Medical School	Newark	New Jersey
United States	Banner University Medical Center - Phoenix Transplant Institute	Newport News	Virginia
United States	Florida Hospital Transplant Institute	Orlando	Florida
United States	IMIC Inc.	Palmetto Bay	Florida
United States	California Liver Research Institute	Pasadena	California
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	St. Joseph's Hospital & Medical Center	Phoenix	Arizona
United States	Stanford University	Redwood City	California
United States	Inland Empire Liver Foundation	Rialto	California
United States	Bon Secours Liver Institute of Virginia	Richmond	Virginia
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	UC Davis GI/Hepatology Clinical Trials Unit	Sacramento	California
United States	University of Utah	Salt Lake City	Utah
United States	American Research Corporation at the Texas Liver Institue	San Antonio	Texas
United States	Methodist Specialty & Transplant Hospital	San Antonio	Texas
United States	San Antonio Military Medical Center	San Antonio	Texas
United States	Scripps Clinic - Torrey Pines	San Diego	California
United States	California Pacific Medical Center	San Francisco	California
United States	University of California San Francisco	San Francisco	California
United States	Swedish Organ Transplant and Liver Center	Seattle	Washington
United States	University of Washington	Seattle	Washington
United States	University of Washington Harborview Medical Center	Seattle	Washington
United States	Tampa General Hospital	Tampa	Florida
United States	University of Arizona Liver Research Institute	Tucson	Arizona
United States	Options Health Research, LLC	Tulsa	Oklahoma
United States	West Haven VA Medical Center	West Haven	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Conatus Pharmaceuticals Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)