A Clinical Trial to Evaluate the Efficacy and Safety of Two Aramchol Doses Versus Placebo in Patients With NASH
Condition: Fatty Liver; Non-Alcoholic Steatohepatitis; Liver Diseases; Liver Fibroses
MeSH terms: Liver Diseases; Fatty Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Fibrosis
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a multicenter, Phase IIb, randomized, double blind, placebo-controlled study designed
      to evaluate the efficacy and safety of two Aramchol doses in subjects that are 18 to 75 years
      of age, with Non-Alcoholic Steatohepatitis (NASH) confirmed by liver biopsy performed in a
      period of 6 months before entering the study, with overweight or obesity and who are pre
      diabetic or type II diabetic.

      Eligible subjects will be enrolled into three treatments arms: Aramchol 400 and 600 mg
      tablets and placebo tablets in ratio 2:2:1.

      The subjects will be evaluated at study sites for 11 scheduled visits during one year (52
      weeks). After completion of the study treatment period, the subjects will be followed for an
      additional period of 13 weeks without study medication (until visit 11 (week 65)).
    

Detailed description: 
      This is a multicenter, Phase IIb, randomized, double blind, placebo-controlled study designed
      to evaluate the efficacy and safety of two Aramchol doses in subjects that are 18 to 75 years
      of age, with Non-Alcoholic Steatohepatitis (NASH) confirmed by liver biopsy performed in a
      period of 6 months before entering the study, with overweight or obesity and who are pre
      diabetic or type II diabetic.

      Eligible subjects will be enrolled into three treatments arms: Aramchol 400 and 600 mg
      tablets and placebo tablets in ratio 2:2:1.

      The subjects will be evaluated at study sites for 11 scheduled visits: at screening (visit
      1(weeks -4 - 0)), baseline (visit 2 (day 0)), visit 3 (week 2), visit 4 week 4), visit 5
      (week 8), visit 6 (week 12), visit 7 (week 24), visit 8 (week 32), visit 9 (week 40) and
      visit 10 (week 52 - (End of Treatment/early termination visit)). After completion of the
      study treatment period, the subjects will be followed for an additional period of 13 weeks
      without study medication (until visit 11 (week 65)).

      During the screening period, the severity of the disease will be evaluated with blood tests,
      liver biopsy and NMRS.

      During the study the following assessments will be performed:

        -  Vital signs will be measured at each study visit.

        -  A physical examination will be performed at the screening visit, 24 weeks, End of
           Treatment/early termination and week 65 visit.

      The following blood tests will be performed: complete blood count (CBC), serum chemistry
      (including electrolytes, liver enzymes, direct and total bilirubin, glucose, lipid profile
      which include triglyceride, cholesterol, HDL, LDL and VLDL, CPK, creatinine, urea, albumin,
      alkaline phosphatase), ESR and urinalysis during the screening visit, baseline, week 2, 4, 8,
      24, 40, 52 and 65 (end of follow up) visits. Serology (HBV, HCV and HIV) will be performed
      during the screening visit. Coagulation (fibrinogen, PT/INR, aPTT) will be measured during
      screening and at baseline, week 24, End of Treatment/early termination and week 65 visits.
      Insulin (HOMA) will be measured during the screening, at week 24 and End of Treatment/early
      termination visits. HbA1C will be measured during the screening, at week 8, 24, 40 and End of
      Treatment/early termination visits. C reactive protein, Leptin and Adiponectin will be
      measured during baseline visit and at end of treatment period. The blood samples taken at
      these visits, will be tested for possible biomarkers. TSH, T3 and T4 will be measured during
      the screening visit. beta-hCG in women of childbearing potential will be performed during the
      screening visit. A serum sample will be collected and kept frozen until study end in case
      special investigation needs to be performed. This sample will be collected during the
      screening and visit 10/Early Termination.

        -  Body weight and waist circumference will be measured in screening, baseline, week 24,
           end of treatment and week 65 visits. Height will be measured during the screening visit.

        -  ECG will be performed during the screening visit, visit 7 (week 24) and end of treatment
           visits.

        -  All subjects will undergo two NMRS scans, at screening and end of treatment visits.

        -  FibroMax test will be performed only if the investigator thinks it is necessary

        -  Liver biopsy will be conducted during the screening and end of treatment visit. The
           biopsy in the screening visit will be performed only if it was not done within the 6
           months prior to this visit.

        -  Metabolomics blood test will be performed at the screening, visit 7 and the
           End-of-Treatment/Early Termination visits. From some consenting patients (about 15) a
           sample from the liver biopsy will be taken for analysis.

        -  Endothelial Function will be conducted in selected sites. The test will be conducted
           during the baseline visit before the study treatment will be given and End of
           Treatment/early termination visit.

        -  Blood sample for Aramchol trough level will be collected (pre-dose) from patients in
           Israel at baseline (visit 2) week 4 (visit 4), week 12 (visit 6), week 24 (visit 7),
           week 40 (visit 9), end of treatment (visit 10) and follow up (visit 11). At selected
           sites in Mexico, USA and Hong Kong one blood sample will be collected (pre-dose) on
           visit 4 (up to 10 subjects per country) to test for trough Aramchol blood level
           differences between populations (e.g., African American, Asian, Hispanic).

        -  Blood sample for gene analysis will be taken from all consenting patients during the
           baseline visit, will be kept frozen and analyzed only at the study end.

        -  Life style questionnaire will be completed at all visits.

        -  Adverse events will be monitored throughout the study.

        -  Concomitant Medications will be monitored throughout the study.

        -  Telephone contacts will be performed on week 16, 20, 28, 36, 44 and 48. An interim
           safety analysis will be conducted as soon as 120 subjects will completed the follow up
           period of 24 weeks under study treatment. An independent DSMB will analyze the safety
           data and recommend a continued course of action. All patients will continue to be
           treated under the study protocol until conclusion of the analysis will be known.

      Safety assessment will include frequency and severity of treatment-emergent AEs, clinically
      significant laboratory abnormalities, ECG changes and physical examination findings.
    

Intervention name(s): Aramchol
Intervention type(s): Drug
Intervention description(s): Subjects will be administered Aramchol as follows:
One tablet of Aramchol 400 mg and one tablet of matching placebo for Aramchol.
One tablet of Aramchol 400 mg and one tablet of Aramchol 200 mg.
Two tablet of Aramchol matching placebo. The tablets should be taken orally in the morning within 30 min after breakfast with a glass of water (250 ml).
Subjects are allowed to omit study drugs up to 3 consecutive days during the study.
Other intervention name(s): Placebo
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: NASH; fibroses; obesity; diabetes