A Clinical Trial to Evaluate the Efficacy and Safety of Two Aramchol Doses Versus Placebo in Patients With NASH

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)).

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.

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