A Clinical Study to Evaluate the Efficacy and Safety of Aramchol in Subjects With NASH (ARMOR)

Study Overview
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Brief Summary
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An Open-Label Part is added: This part will enroll in selected sites which are less affected by the COVID-19 pandemic. 150 subjects with NASH and fibrosis confirmed by liver histology (F1-F3) will be randomized into 3 groups according to the post-baseline biopsy. The objective of the Open-Label Part is: To evaluate the safety and PK of twice daily administration (BID) of Aramchol 300mg in subjects with NASH and liver fibrosis. To explore the kinetics of histological outcome measures and Non-Invasive Tests (NITs) associated with NASH and fibrosis for the treatment duration of 24, 48 and 72 weeks. All patients will be allocated to Aramchol. Double Blind Part: This part is double blind, placebo controlled randomized in subjects with NASH and fibrosis stages 2-3 who are overweight or obese and have prediabetes or type 2 diabetes. The primary objectives of this part of the study are to evaluate the effect of Aramchol as compared to placebo on NASH resolution, fibrosis improvement and clinical outcomes related to progression of liver disease. Subjects will be randomized to receive Aramchol 300mg BID or matching placebo in a 2:1 randomization ratio.

Official Title
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A Phase 3, Multinational, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Study to Evaluate the Efficacy and Safety of Aramchol in Subjects With Nonalcoholic Steatohepatitis (NASH) With Open-Label Part to Evaluate the Safety, PK and Treatment Response Kinetics of Aramchol. The ARMOR Study

Conditions
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Nonalcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: Aramchol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female age 18 to 75 years Histological confirmation of NASH on a diagnostic liver biopsy by central reading of the slides (biopsy obtained within 6 months prior to randomization or during the screening period) Total NAS Score 4 or more with at least 1 in each component of the NAS Score (steatosis ≥1 AND inflammation ≥1 AND ballooning ≥1) Fibrosis Stage must be 2 or 3 (Open-Label Part may include up to 30 subjects with fibrosis stage 1) Body mass index (BMI) between 25kg/m2 and 40 kg/m2 (Open Label part: BMI <40 kg/m2) AST>20 IU/L Type 2 diabetes mellitus or prediabetes (Open Label Part only: Type 2 diabetes or prediabetes is not an inclusion criteria) For subjects with type 2 diabetes, glycemia must be controlled Females of childbearing potential must practice a highly effective method of contraception throughout the study period and for 1 month after treatment discontinuation. Able to understand the nature of the study and to provide signature of the written informed consent. Key Exclusion Criteria: Histologically documented liver cirrhosis (fibrosis stage 4) Inability or unwillingness to undergo a liver biopsy Abnormal synthetic liver function ALT or AST >5× upper limit of normal (ULN) Platelet count < 150,000mm3 Alkaline phosphatase ≥2× ULN Known or suspected hepatocellular carcinoma (HCC) Model for End-Stage Liver Disease (MELD) score > 12 Prior history or presence of decompensated liver disease Other (acute or chronic) coexisting liver disease based on medical history and/or centralized review of liver histology) Known alcohol and/or any other drug abuse or dependence in the last five years Weight loss of more than 5% within 3 months prior to screening History of bariatric surgery within 5 years of liver biopsy or planned surgery for weight reduction Treatment with drugs that may cause NAFLD within 12 months prior to liver biopsy Treatment with some anti-diabetic medications; Unless started prior to biopsy (timeframe depending on drug) and stable Current or planned treatment with immunosuppressive drugs Evidence of any other unstable or untreated clinically significant disease Uncontrolled hypertension Any other condition that in the opinion of the Investigator warrants exclusion from the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In the Double-Blind part of the study, subjects will be randomized in a ratio of 2:1 to receive Aramchol 300mg BID or matching placebo, respectively. In the Open Label part of the study, there will be a single group of 150 subjects (expected) all receiving Aramchol 300mg BID.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aramchol<br>Aramchol 300 mg oral tablet | Drug: Aramchol<br>* Aramchol 300 mg BID<br>|
| Placebo Comparator: Placebo<br>Placebo matching oral tablet | Drug: Placebo<br>* Placebo BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Open label part: Kinetics of histological outcome measures | The primary endpoints are the kinetics of the following histological outcome measures for treatment duration of 24, 48 and 72 weeks and potentially following a 2nd post-baseline biopsy at weeks 72 or 96 or 120, respectively: Improvement in Fibrosis defined as the Proportion (%) of subjects with improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation or steatosis) Resolution of NASH defined as the Proportion (%) of subjects with resolution of NASH (defined by ballooning of 0 and inflammation 0-1) and no worsening of liver fibrosis on NASH CRN fibrosis score (≥ 1 stage increase). | Up to 72 or 120 weeks | 
| Double Blind Part: To evaluate the effect of Aramchol compared to placebo on liver histology by assessing the following primary endpoints: | Resolution of NASH defined as the Proportion (%) of subjects with resolution of NASH (defined by Ballooning of 0 and inflammation 0-1) and no worsening of liver fibrosis, or Improvement in Fibrosis defined as the Proportion (%) of subjects with improvement in liver fibrosis greater than or equal to one stage and no worsening of steatohepatitis. | 72 weeks | 
| Double Blind Part: To evaluate the effect of Aramchol compared to placebo on composite long-term outcome | Proportion (%) of subjects experiencing at least 1 of the following events: All-cause mortality, Liver transplant, Histological progression to cirrhosis, MELD score >15, Hospitalization due to hepatic decompensation event(s). | at End of Study, latest at 5 years from last subject's randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fibrosis, liver fibrosis, diabetes, obesity