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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.

Tracking Information
First Submitted Date  ICMJE February 10, 2016
First Posted Date  ICMJE February 19, 2016
Last Update Posted Date August 19, 2019
Actual Study Start Date  ICMJE January 26, 2016
Actual Primary Completion Date January 29, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 16, 2016)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 16, 2016)
  • 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
  • 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
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Emricasan, a Caspase Inhibitor, for Evaluation in Subjects With Non-Alcoholic Steatohepatitis (NASH) Fibrosis
Official Title  ICMJE 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
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Non-alcoholic Steatohepatitis
  • Fibrosis
  • Liver Diseases
Intervention  ICMJE
  • 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
  • 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
  • Drug: Placebo
    Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with a matching placebo twice a day.
Study Arms  ICMJE
  • Active Comparator: Emricasan (5 mg)
    Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (5 mg) twice a day.
    Intervention: Drug: Emricasan (5 mg)
  • Active Comparator: Emricasan (50 mg)
    Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with emricasan (50 mg) twice a day.
    Intervention: Drug: Emricasan (50 mg)
  • Placebo Comparator: Matching Placebo
    Subjects with Non-alcoholic Steatohepatitis (NASH) Fibrosis will be administered orally with a matching placebo twice a day.
    Intervention: Drug: Placebo
Publications * Harrison SA, Goodman Z, Jabbar A, Vemulapalli R, Younes ZH, Freilich B, Sheikh MY, Schattenberg JM, Kayali Z, Zivony A, Sheikh A, Garcia-Samaniego J, Satapathy SK, Therapondos G, Mena E, Schuppan D, Robinson J, Chan JL, Hagerty DT, Sanyal AJ. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J Hepatol. 2020 May;72(5):816-827. doi: 10.1016/j.jhep.2019.11.024. Epub 2019 Dec 27.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 15, 2019)
318
Original Estimated Enrollment  ICMJE
 (submitted: February 16, 2016)
330
Actual Study Completion Date  ICMJE February 28, 2019
Actual Primary Completion Date January 29, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02686762
Other Study ID Numbers  ICMJE IDN-6556-12
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Conatus Pharmaceuticals Inc.
Study Sponsor  ICMJE Conatus Pharmaceuticals Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Jean L Chan, MD Conatus Pharmaceuticals Inc.
PRS Account Conatus Pharmaceuticals Inc.
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP