Clinical trial NCT02960204: Emricasan, an Oral Caspase Inhibitor, in Subjects With NASH Cirrhosis and Severe Portal Hypertension
Official title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, an Oral Caspase Inhibitor, in Subjects With Non-Alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cirrhosis
Portal Hypertension
Non-alcoholic Steatohepatitis
Keywords: cirrhosis
Portal Hypertension
Non-alcoholic Steatohepatitis
Liver cirrhosis
Lead sponsor: Histogen
Sponsor class: INDUSTRY
First posted: 2016-11-09
Enrollment: 263
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, randomized, double-blind, placebo-controlled trial involving subjects with NASH cirrhosis and severe portal hypertension (defined as HVPG ≥12 mmHg as determined by the central reader assigned to this study). Upon successful screening, subjects will be randomized to receive either emricasan 50 mg BID, 25 mg BID, or 5 mg BID or matching placebo BID.


Eligibility criteria: Inclusion Criteria:

* 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.
* Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral hepatitis, alcoholic liver disease, etc.)
* Compensated cirrhosis OR Decompensated cirrhosis with no more than 1 prior significant decompensating event
* Severe portal hypertension defined as HVPG ≥12 mmHg
* Subjects who are on NSBB, nitrates, diuretics, lactulose, rifaximin, or statins must be on a stable dose for at least 3 months prior to Day 1
* 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

Exclusion Criteria:

* Evidence of severe decompensation
* Severe hepatic impairment defined as a Child-Pugh score ≥10
* ALT (alanine transaminase) \> 3 times upper limit of normal (ULN) or AST (aspartate transaminase) \>5 times ULN during screening
* Estimated creatinine clearance \<30 mL/min
* Prior transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure
* Known portal vein thrombosis
* Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 months, unless resolved following cholecystectomy
* Current use of medications that are considered inhibitors of OATP1B1 and OATP1B3 transporters
* Alpha-fetoprotein \>50 ng/mL
* History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QTcF interval of \>500 msec
* History of or active malignancies, other than those successfully treated with curative intent and believed to be cured
* Prior liver transplant
* Change in diabetes medications or vitamin E within 3 months of screening
* Uncontrolled diabetes mellitus (HbA1c \>9%) within 3 months of screening
* Significant systemic or major illness other than liver disease
* HIV infection
* Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of prescription drugs within 1 year of screening
* If female: planned or known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding
* Previous treatment with emricasan or active investigational medication (except methacetin) in a clinical trial within 3 months prior to Day 1

Primary outcomes:
measure: Mean Change in Hepatic Venous Pressure Gradient (HVPG)
timeFrame: Baseline to Week 24
Secondary outcomes:
measure: Improvement of HVPG Response Using a 20% Reduction From Baseline
timeFrame: Baseline to Week 24
measure: Caspase 3/7
timeFrame: Baseline to Week 24, Baseline to Week 48
measure: Alanine Aminotransferase (ALT)
timeFrame: Baseline to Week 24 and Baseline to Week 48
Other outcomes:
Locations:
city: Pasadena
country: United States
facility: Pasadena
state: California
city: Rialto
country: United States
facility: Rialto
state: California
city: Palmetto Bay
country: United States
facility: Palmetto Bay
state: Florida
city: Atlanta
country: United States
facility: Atlanta
state: Georgia
city: Clive
country: United States
facility: Clive
state: Iowa
city: Baltimore
country: United States
facility: Baltimore
state: Maryland
city: Detroit
country: United States
facility: Detroit
state: Michigan
city: Rochester
country: United States
facility: Rochester
state: Minnesota
city: Saint Paul
country: United States
facility: Saint Paul
state: Minnesota
city: Kansas City
country: United States
facility: Kansas City
state: Missouri
city: Durham
country: United States
facility: Durham
state: North Carolina
city: Philadelphia
country: United States
facility: Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Philadelphia
state: Pennsylvania
city: Germantown
country: United States
facility: Germantown
state: Tennessee
city: Arlington
country: United States
facility: Arlington
state: Texas
city: Houston
country: United States
facility: Houston
state: Texas
city: San Antonio
country: United States
facility: San Antonio
state: Texas
city: San Antonio
country: United States
facility: San Antonio
state: Texas
city: Norfolk
country: United States
facility: Norfolk
state: Virginia
city: Richmond
country: United States
facility: Richmond
state: Virginia
city: Richmond
country: United States
facility: Richmond
state: Virginia
city: Seattle
country: United States
facility: Seattle, Washington
state: Washington
city: Bonn
country: Germany
facility: Bonn
city: Halle (Saale)
country: Germany
facility: Halle (Saale)
city: Leipzig
country: Germany
facility: Leipzig
city: Mainz
country: Germany
facility: Mainz
city: Münster
country: Germany
facility: Münster
city: Barcelona
country: Spain
facility: Barcelona
city: Barcelona
country: Spain
facility: Barcelona
city: Madrid
country: Spain
facility: Madrid
city: Madrid
country: Spain
facility: Madrid
city: Madrid
country: Spain
facility: Madrid
city: Majadahonda
country: Spain
facility: Majadahonda
city: San Sebastian
country: Spain
facility: San Sebastian
city: Santander
country: Spain
facility: Santander
city: Valencia
country: Spain
facility: Valencia
city: Valencia
country: Spain
facility: Valencia
Study officials:
affiliation: Histogen
name: Jeanette M Wetzel
role: STUDY_DIRECTOR
affiliation: Histogen
name: Samuel Mboggo
role: STUDY_DIRECTOR
affiliation: Histogen
name: Ruqayyah Abdulrahoof
role: STUDY_DIRECTOR
References:
citation: Garcia-Tsao G, Bosch J, Kayali Z, Harrison SA, Abdelmalek MF, Lawitz E, Satapathy SK, Ghabril M, Shiffman ML, Younes ZH, Thuluvath PJ, Berzigotti A, Albillos A, Robinson JM, Hagerty DT, Chan JL, Sanyal AJ; IDN-6556-14 Investigators(double dagger). Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension. J Hepatol. 2020 May;72(5):885-895. doi: 10.1016/j.jhep.2019.12.010. Epub 2019 Dec 21.