Clinical trial NCT03205345: Emricasan, a Caspase Inhibitor, for Treatment of Subjects With Decompensated NASH Cirrhosis
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Decompensated Cirrhosis
Keywords: Cirrhosis
NASH Cirrhosis
Decompensated NASH cirrhosis
Cirrhosis, Liver
Non-Alcoholic Fatty Liver Disease
Lead sponsor: Conatus Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2017-07-02
Enrollment: 210
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 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Comparison of the effect of emricasan on improving event-free survival relative to placebo, based on a composite clinical endpoint
timeFrame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
Secondary outcomes:
measure: Improvement in MELD score
timeFrame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
measure: Improvement in Child-Pugh scores
timeFrame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
measure: Reduction of the proportion of subjects with MELD score progression
timeFrame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
measure: Decrease in new decompensation events
timeFrame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
measure: Decrease in liver transplantation rates
timeFrame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
measure: Decrease in all-cause and liver specific mortality
timeFrame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
measure: Improvement in health-related quality of life (QOL) as measured by Short Form-36
timeFrame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
measure: Improvement in liver metabolic function as measured by Methacetin Breath Test (MBT)
timeFrame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks)
Other outcomes:
Locations:
city: Chandler
country: United States
facility: The Institute for Liver Health
state: Arizona
city: Phoenix
country: United States
facility: St. Joseph's Hospital & Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Liver Research Institute
state: Arizona
city: Fresno
country: United States
facility: University of California, San Francisco-Fresno
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Pfleger Liver Institute
state: California
city: Pasadena
country: United States
facility: California Liver Research Institute
state: California
city: Redwood City
country: United States
facility: Stanford University
state: California
city: Rialto
country: United States
facility: Inland Empire Liver Foundation
state: California
city: Sacramento
country: United States
facility: UC Davis GI/Hepatology Clinical Trials Unit
state: California
city: San Diego
country: United States
facility: Scripps Clinic - Torrey Pines
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Colorado Springs
country: United States
facility: Peak Enterology Associates
state: Colorado
city: West Haven
country: United States
facility: West Haven VA Medical Center
state: Connecticut
city: Gainesville
country: United States
facility: UF Hepatology Research at CTRB
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Lakewood Ranch
country: United States
facility: Florida Research Institute
state: Florida
city: Miami
country: United States
facility: Schiff Center for Liver Disease/University of Miami
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Transplant Institute
state: Florida
city: Palmetto Bay
country: United States
facility: IMIC Inc.
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Atlanta
country: United States
facility: Piedmont Transplant Institute
state: Georgia
city: Marietta
country: United States
facility: Gastrointestinal Specialists of Georgia
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Albany
country: United States
facility: Aquiant Research
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics/ Internal Medicine
state: Iowa
city: Bastrop
country: United States
facility: Delta Research Partners
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
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 (WRNMMC)
state: Maryland
city: Catonsville
country: United States
facility: Digestive Disease Associates, PA
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: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center, Division of Digestive Diseases
state: Mississippi
city: Kansas City
country: United States
facility: Kansas City Research Institute
state: Missouri
city: Newark
country: United States
facility: Rutgers New Jersey Medical School
state: New Jersey
city: Manhasset
country: United States
facility: Northwell Health Inc., Sandra Atlas Bass Center for Liver Diseases.
state: New York
city: New York
country: United States
facility: NYU Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Columbia University Medical Center - Center for Liver Disease and Transplantation
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
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
state: North Carolina
city: Morehead City
country: United States
facility: Diabetes & Endocrinology Consultants, PC
state: North Carolina
city: Cincinnati
country: United States
facility: UC Health/ UCPC LLC
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: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: GHS Gastroenterology and Liver Center
state: South Carolina
city: Chattanooga
country: United States
facility: ClinSearch, LLC
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Arlington
country: United States
facility: Texas Clinical Research Institute
state: Texas
city: Dallas
country: United States
facility: Methodist Health System 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 Scott & White Research Institute
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine - Advanced Liver Therapies
state: Texas
city: Houston
country: United States
facility: Liver Associates of Texas, P.A.
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: Methodist Specialty & Transplant Hospital
state: Texas
city: San Antonio
country: United States
facility: San Antonio Military Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Leesburg
country: United States
facility: Emeritas Research Group LLC
state: Virginia
city: Newport News
country: United States
facility: Banner University Medical Center - Phoenix Transplant Institute
state: Virginia
city: Richmond
country: United States
facility: Bon Secours Liver Institute of Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Swedish Organ Transplant and Liver Center
state: Washington
city: Seattle
country: United States
facility: University of Washington Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: Conatus Pharmaceuticals Inc.
name: Jean L Chan, MD
role: STUDY_DIRECTOR
References:
citation: Frenette C, Kayali Z, Mena E, Mantry PS, Lucas KJ, Neff G, Rodriguez M, Thuluvath PJ, Weinberg E, Bhandari BR, Robinson J, Wedick N, Chan JL, Hagerty DT, Kowdley KV; IDN-6556-17 Study Investigators. Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis. J Hepatol. 2021 Feb;74(2):274-282. doi: 10.1016/j.jhep.2020.09.029. Epub 2020 Oct 8.