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

Phase 2

Completed

• Conditions: Non-alcoholic Steatohepatitis; Liver Diseases; Fibrosis
• Interventions: Drug: Emricasan (50 mg); Drug: Emricasan (5 mg); Drug: Placebo

• Registration Number: NCT02686762
• Lead Sponsor: Conatus Pharmaceuticals Inc.

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2016-01-26
• Study First Submitted: 2016-02-10
• Study First Submitted QC: 2016-02-16
• Study First Posted: 2016-02-19
• Primary Completion: 2019-01-29
• Study Completion: 2019-02-28
• Status Verified: 2019-08
• Last Update Submitted: 2019-08-15
• Last Update Posted: 2019-08-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 318

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Emricasan (50 mg)	Emricasan (50 mg)	Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (50 mg) twice a day.
Emricasan (5 mg)	Emricasan (5 mg)	Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (5 mg) twice a day.
Matching Placebo	Placebo	Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with a matching placebo twice a day.

Primary Outcome Measures

Name	Time	Method
Fibrosis improvement by at least one stage without worsening of steatohepatitis	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

Name	Time	Method
Improvement in the Non-alcoholic fatty liver disease (NAFLD) Activity Score	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
Steatohepatitis resolution (based on liver biopsy)	Baseline & Week 72	The proportion of subjects who resolve steatohepatitis without worsening of fibrosis in the emricasan group compared to placebo
Caspase 3/7 Relative Light Units and Alanine aminotransferase (ALT)	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.

Trial Locations

Locations (103)

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

University of Arizona Clinical and Translational Sciences Research Center; 🇺🇸 Tucson, Arizona, United States

Preferred Research Partners, Inc.; 🇺🇸 Little Rock, Arkansas, United States

Fresno Clinical Research Center; 🇺🇸 Freestone, California, United States

UCLA The Pfleger Liver Institute; 🇺🇸 Los Angeles, California, United States

Gastrointestinal Biosciences; 🇺🇸 Los Angeles, California, United States

Surinder Singh Saini, M.D., Inc.; 🇺🇸 Newport Beach, California, United States

California Liver Research Institute; 🇺🇸 Pasadena, California, United States

Inland Empire Liver Foundation; 🇺🇸 Rialto, California, United States

University of California Davis Medical Center; 🇺🇸 Sacramento, California, United States

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