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

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ClinicalTrials.gov Identifier: NCT02686762
Recruitment Status : Completed
First Posted : February 19, 2016
Last Update Posted : August 19, 2019
Sponsor:
Information provided by (Responsible Party):
Conatus Pharmaceuticals Inc.

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
Non-alcoholic Steatohepatitis Fibrosis Liver Diseases Drug: Emricasan (5 mg) Drug: Emricasan (50 mg) Drug: Placebo Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 318 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : January 26, 2016
Actual Primary Completion Date : January 29, 2019
Actual Study Completion Date : February 28, 2019

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Emricasan (5 mg)
Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (5 mg) twice a day.
 Drug: Emricasan (5 mg)
Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (5 mg) twice a day.
Other Name: IDN-6556
Active Comparator: Emricasan (50 mg)
Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (50 mg) twice a day.
 Drug: Emricasan (50 mg)
Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (50 mg) twice a day.
Other Name: IDN-6556
Placebo Comparator: Matching Placebo
Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with a matching placebo twice a day.
 Drug: Placebo
Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with a matching placebo twice a day.


Outcome Measures
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Primary Outcome Measures :
  1. Fibrosis improvement by at least one stage without worsening of steatohepatitis [ Time Frame: Week 72 ]
    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


Secondary Outcome Measures :
  1. Steatohepatitis resolution (based on liver biopsy) [ Time Frame: Baseline & Week 72 ]
    The proportion of subjects who resolve steatohepatitis without worsening of fibrosis in the emricasan group compared to placebo

  2. Improvement in the Non-alcoholic fatty liver disease (NAFLD) Activity Score [ Time Frame: Baseline & Week 72 ]
    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

  3. Caspase 3/7 Relative Light Units and Alanine aminotransferase (ALT) [ Time Frame: Day 1, week 4, 24, 48, and 72 ]
    To asses whether emricasan compared to placebo improves biomarkers Caspase 3/7 RLU and ALT Unit/Liter (U/L) in subjects with NASH fibrosis.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02686762


Locations
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Sponsors and Collaborators
Conatus Pharmaceuticals Inc.
Investigators
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Study Chair: Jean L Chan, MD Conatus Pharmaceuticals Inc.
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Conatus Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT02686762    
Other Study ID Numbers: IDN-6556-12
First Posted: February 19, 2016    Key Record Dates
Last Update Posted: August 19, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Conatus Pharmaceuticals Inc.:
NASH
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
 Fibrosis
Pathologic Processes
Digestive System Diseases