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Emricasan, an Oral Caspase Inhibitor, in Subjects With NASH Cirrhosis and Severe Portal Hypertension (ENCORE-PH)

Primary Purpose

Cirrhosis, Portal Hypertension, Non-alcoholic Steatohepatitis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Emricasan
Placebo
Sponsored by
Histogen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cirrhosis focused on measuring cirrhosis, Portal Hypertension, Non-alcoholic Steatohepatitis, Liver cirrhosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Pasadena
  • Rialto
  • Palmetto Bay
  • Atlanta
  • Clive
  • Baltimore
  • Detroit
  • Rochester
  • Saint Paul
  • Kansas City
  • Durham
  • Philadelphia
  • Philadelphia
  • Germantown
  • Arlington
  • Houston
  • San Antonio
  • San Antonio
  • Norfolk
  • Richmond
  • Richmond
  • Seattle, Washington
  • Bonn
  • Halle (Saale)
  • Leipzig
  • Mainz
  • Münster
  • Barcelona
  • Barcelona
  • Madrid
  • Madrid
  • Madrid
  • Majadahonda
  • San Sebastian
  • Santander
  • Valencia
  • Valencia

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Emricasan (5 mg)

Emricasan (25 mg)

Emricasan (50 mg)

Matching Placebo

Arm Description

Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (5 mg) twice a day.

Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (25 mg) twice a day.

Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (50 mg) twice a day.

Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with a matching placebo twice a day.

Outcomes

Primary Outcome Measures

Mean Change in Hepatic Venous Pressure Gradient (HVPG)
To assess the mean change from baseline to Week 24 in hepatic venous pressure gradient (HVPG)

Secondary Outcome Measures

Improvement of HVPG Response Using a 20% Reduction From Baseline
To assess subjects who have at least a 20 percent reduction from baseline in HVPG
Caspase 3/7
To assess whether number of Caspase 3/7 biomarkers is affected by emricasan as compared to placebo
Alanine Aminotransferase (ALT)
To assess whether amount of non-specific (ALT) biomarkers are affected by emricasan compared to placebo

Full Information

First Posted
July 29, 2016
Last Updated
January 13, 2022
Sponsor
Histogen
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1. Study Identification

Unique Protocol Identification Number
NCT02960204
Brief Title
Emricasan, an Oral Caspase Inhibitor, in Subjects With NASH Cirrhosis and Severe Portal Hypertension
Acronym
ENCORE-PH
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

2. Study Status

Record Verification Date
December 2021
Overall Recruitment Status
Completed
Study Start Date
October 17, 2016 (Actual)
Primary Completion Date
October 2, 2018 (Actual)
Study Completion Date
April 8, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Histogen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhosis, Portal Hypertension, Non-alcoholic Steatohepatitis
Keywords
cirrhosis, Portal Hypertension, Non-alcoholic Steatohepatitis, Liver cirrhosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
263 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Emricasan (5 mg)
Arm Type
Active Comparator
Arm Description
Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (5 mg) twice a day.
Arm Title
Emricasan (25 mg)
Arm Type
Active Comparator
Arm Description
Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (25 mg) twice a day.
Arm Title
Emricasan (50 mg)
Arm Type
Active Comparator
Arm Description
Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (50 mg) twice a day.
Arm Title
Matching Placebo
Arm Type
Placebo Comparator
Arm Description
Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with a matching placebo twice a day.
Intervention Type
Drug
Intervention Name(s)
Emricasan
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Mean Change in Hepatic Venous Pressure Gradient (HVPG)
Description
To assess the mean change from baseline to Week 24 in hepatic venous pressure gradient (HVPG)
Time Frame
Baseline to Week 24
Secondary Outcome Measure Information:
Title
Improvement of HVPG Response Using a 20% Reduction From Baseline
Description
To assess subjects who have at least a 20 percent reduction from baseline in HVPG
Time Frame
Baseline to Week 24
Title
Caspase 3/7
Description
To assess whether number of Caspase 3/7 biomarkers is affected by emricasan as compared to placebo
Time Frame
Baseline to Week 24, Baseline to Week 48
Title
Alanine Aminotransferase (ALT)
Description
To assess whether amount of non-specific (ALT) biomarkers are affected by emricasan compared to placebo
Time Frame
Baseline to Week 24 and Baseline to Week 48

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeanette M Wetzel
Organizational Affiliation
Histogen
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Samuel Mboggo
Organizational Affiliation
Histogen
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Ruqayyah Abdulrahoof
Organizational Affiliation
Histogen
Official's Role
Study Director
Facility Information:
Facility Name
Pasadena
City
Pasadena
State/Province
California
ZIP/Postal Code
91105
Country
United States
Facility Name
Rialto
City
Rialto
State/Province
California
ZIP/Postal Code
92377
Country
United States
Facility Name
Palmetto Bay
City
Palmetto Bay
State/Province
Florida
ZIP/Postal Code
33157
Country
United States
Facility Name
Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30309
Country
United States
Facility Name
Clive
City
Clive
State/Province
Iowa
ZIP/Postal Code
50325
Country
United States
Facility Name
Baltimore
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21202
Country
United States
Facility Name
Detroit
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Saint Paul
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55114
Country
United States
Facility Name
Kansas City
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64131
Country
United States
Facility Name
Durham
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19141
Country
United States
Facility Name
Germantown
City
Germantown
State/Province
Tennessee
ZIP/Postal Code
38138
Country
United States
Facility Name
Arlington
City
Arlington
State/Province
Texas
ZIP/Postal Code
76012
Country
United States
Facility Name
Houston
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78215
Country
United States
Facility Name
San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78233
Country
United States
Facility Name
Norfolk
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23502
Country
United States
Facility Name
Richmond
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23226
Country
United States
Facility Name
Richmond
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23249
Country
United States
Facility Name
Seattle, Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
Facility Name
Bonn
City
Bonn
ZIP/Postal Code
53127
Country
Germany
Facility Name
Halle (Saale)
City
Halle (Saale)
ZIP/Postal Code
06120
Country
Germany
Facility Name
Leipzig
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Mainz
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
Münster
City
Münster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Barcelona
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Madrid
City
Madrid
ZIP/Postal Code
28006
Country
Spain
Facility Name
Madrid
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
Madrid
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Majadahonda
City
Majadahonda
ZIP/Postal Code
28222
Country
Spain
Facility Name
San Sebastian
City
San Sebastian
ZIP/Postal Code
20014
Country
Spain
Facility Name
Santander
City
Santander
ZIP/Postal Code
39008
Country
Spain
Facility Name
Valencia
City
Valencia
ZIP/Postal Code
46010
Country
Spain
Facility Name
Valencia
City
Valencia
ZIP/Postal Code
46104
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
There is no plan to share this data with outside researchers
Citations:
PubMed Identifier
31870950
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.
Results Reference
result

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Emricasan, an Oral Caspase Inhibitor, in Subjects With NASH Cirrhosis and Severe Portal Hypertension

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