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
Intervention: Aramchol
Intervention description: 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 247.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: NASH; fibroses; obesity; diabetes

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)).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female age 18 to 75 years.

          2. BMI between 25kg/m2 to 40kg/m2 or waist circumference between 88 cm to 200 cm for
             women, and between 102 cm to 200 cm for men. If there is deviation above the upper
             limit, please consult the MRI center, to ensure that the machine is suitable for the
             patient.

          3. Known type II Diabetes Mellitus or pre-Diabetes according to American Diabetes
             Association. One of the following 3 criteria is needed for pre-Diabetes: Fasting
             Plasma Glucose > 100mg/dl (5.5 mmol/l) or 2hPG following 75g OGTT > 140 (7.8 mmol/l)
             mg/dl or HbA1c > 5.7%. HbA1c can be repeated at Investigator's discretion.

          4. Histologically proven Steatohepatitis on a diagnostic liver biopsy performed either
             during screening or within 6 months before screening visit, confirmed by central
             laboratory reading of the slides.(Steatosis ≥1 + inflammation ≥1 + ballooning
             ≥1).Total activity NAS score of 4 or more.

          5. Liver fat concentration in the liver of 5.5% or more as measured by NMRS.

          6. Biopsies with an activity NAS score of 4 or more.

          7. Normal synthetic liver function (serum albumin >3.2g/dl, INR 0.8-1.2, conjugated
             bilirubin < 35 µmol/L).

          8. Understanding the nature of the study and signature of the written informed consent.

          9. Negative pregnancy test at study entry for females of child bearing potential.

         10. Females of child bearing potential practicing reliable contraception throughout the
             study period (including oral contraceptives) as well as negative pregnancy test at
             study entry.

         11. Hypertensive patients must be well controlled by stable dose of anti-hypertensive
             medication for at least 2 months prior to screening.

         12. Patients previously treated with vitamin E (>400IU/day), Polyunsaturated fatty acid
             (>2g/day) or Ursodeoxycholic acid or fish oil can be included if stopped or at least
             maintained on stable dose at least 3 months prior to diagnostic liver biopsy (and are
             not started during the trial). These treatments-dosages are allowed if they were
             stable for at least 12 months prior to biopsy and can remain stable throughout the
             study. (Dosages less than the amounts stated above are allowed without washout- or
             stable-period restrictions).

         13. For patients with type II Diabetes, glycaemia must be controlled (Glycosylated
             Hemoglobin A1c ≤9%) while any HbA1c change should not exceed 1.5% during 6 months
             prior to enrolment). Treatments with anti-diabetic medications (except for those
             mentioned in Exclusion 16) are permitted if glycaemia is self-monitored by the
             patient. HbA1c can be repeated at Investigator's discretion.

        Exclusion Criteria:

          1. Patients with other active (acute or chronic) liver disease other than NASH (e.g.
             viral hepatitis, unless eradicated at least 3 years prior to screening; genetic
             hemochromatosis; Wilson disease; alpha 1antitripsin deficiency; alcohol liver disease;
             drug-induced liver disease) at the time of randomization.

          2. Patients with clinically or histologically documented liver cirrhosis

          3. Known alcohol and/or any other drug abuse or dependence in the last five years.

          4. Known history or presence of clinically significant cardiovascular, gastrointestinal,
             metabolic other than Diabetes Mellitus, neurologic, pulmonary, endocrine, psychiatric,
             neoplastic disorder or nephrotic syndrome, that in the opinion of the Investigator
             warrant exclusion from the study.

          5. Patients with familial (i.e., genetic) hypertriglyceridemia and familial (i.e.,
             genetic) hypercholesterolemia.

          6. History or presence of any disease or condition known to interfere with the absorption
             distribution, metabolism or excretion of drugs including bile salt metabolites (e.g.
             inflammatory bowel disease (IBD)), previous intestinal (ileal or colonic) operation,
             chronic pancreatitis, celiac disease or previous vagotomy. Ongoing Chronic
             constipation

          7. Patients with heart or brain pacemaker (i.e., implantable neurological devices).

          8. Surgery during the last three month before screening which involved stent implantation
             of metal devices (e.g. knee, hip etc.)

          9. Weight loss of more than 5% within 6 months prior to randomization.

         10. History of bariatric surgery within 5 years of liver biopsy.

         11. Uncontrolled arterial hypertension.

         12. Women who are pregnant and breast feeding.

         13. Diabetes Mellitus other than type II (type I, endocrinopathy, genetic syndromes etc.).

         14. Patients with HIV infection.

         15. Daily alcohol intake >20 g/day for women and >30 g/day for men (on average per day) as
             per medical history.

         16. Treatment with other anti-diabetic medications:

             GLP-1 receptor agonists and Thiazolidinediones (TZDs), unless started at least 12
             months prior to biopsy and on stable dose for 6 months. In case of GLP-1 receptor
             agonists stopped, it should be at least 6 months before biopsy as per medical history.

         17. SGLT-2 Inhibitors, Metformin, fibrates, statins, insulin, DPP-4 inhibitors and
             sulfonylurea unless prescribed dose has been stable for the last 6 months prior to the
             biopsy.

         18. Treatment with Valproic acid, Tamoxifen, Methotrexate, Amiodarone or chronic treatment
             with anti-cholinergic agents, corticosteroids, high dose estrogen and tetracycline
             within 12 months prior to the screening visit.

         19. Chronic treatment with antibiotics (e.g. Rifaximin).

         20. Homeopathic and/or alternative treatments. Any treatment should be stopped during the
             screening period at least 48 hours before randomization.

         21. Uncontrolled hypothyroidism defined as Thyroid Stimulating hormone >2X the upper limit
             of normal (ULN). Thyroid dysfunction controlled for at least 6 months prior to
             screening is permitted.

         22. Patients with renal dysfunction eGFR< 40.

         23. Unexplained serum creatine phosphokinase (CPK) >3X the upper limit of normal (UNL).
             Patients with a reason for CPK elevation may have the measurement repeated prior to
             randomization; a CPK retest > 3X ULN leads to exclusion.

         24. Patients with condition(s) that makes them unsuitable to perform the NMRS (as
             determined by the PI or the MRI facility).

         25. Hypersensitivity to Aramchol or to any of the excipients in the tablets

         26. Hypersensitivity to cholic acid or bile acid sequestrants