Inclusion and Exclusion Criteria: NASH ARREST Drug Study

Inclusion Criteria

  • Male or female age 18 to 75 years
  • BMI of ≥25 and ≤40 kg/m2 or waist circumference >88<200 cm for women and >102<200 cm for men
  • Known Type 2 diabetes mellitus or pre-diabetes according to American Diabetes Association. One of the following three criteria is needed for pre-diabetic: 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 percent
  • Histologically proven steatohepatitis on a diagnostic liver biopsy performed within six months before screening visit, confirmed by central laboratory reading of the slides (steatosis >5 percent + lobular inflammation, any ballooning, any amount)
  • Liver fat concentration of 5.5 percent or more as measured by nuclear magnetic resonance spectroscopy
  • Biopsies with an nonalcoholic fatty liver disease activity score of 4 or more
  • Normal synthetic liver function (serum albumin >3.5 g/l, INR 0.8-1.3)
  • Understanding the nature of the study and signature of the written informed consent
  • Negative pregnancy test at study entry for females of child-bearing potential
  • Females of child bearing potential practicing reliable birth control throughout the study period. If barrier methods are used, it is recommended to practice two methods (e.g., male condom + female diaphragm with spermicide)
  • Hypertension in patients must be well controlled by stable dose of anti-hypertensive medication for at least two months prior to screening (and the stable dose must be maintained throughout the study)
  • Patients previously treated with vitamin E (>400 IU/day), polyunsaturated fatty acid (>2 g/day) ursodeoxycholic acid or fish oil can be included if drugs are stopped at least three months prior to diagnostic liver biopsy and up to the end of study unless on stable dose for the past 12 months prior to biopsy
  • For patients with Type 2 diabetes, glycaemia must be controlled (glycosylated hemoglobin A1c ≤9 percent while any HbA1c changes should not exceed 1.5 percent during the six months prior to enrollment). Treatments with metformin, sulfonylurea and insulin are authorized. Sulfonylurea and insulin are permitted if glycaemia is self-monitored by the patient

Exclusion Criteria

  • Patients with other active (acute or chronic) liver disease other than NASH (e.g., viral hepatitis, genetic hemochromatosis, Wilson disease, alpha-1 antitripsin deficiency, alcohol liver disease, drug induced liver disease) at the time of randomization
  • Patients who have liver cirrhosis (Clinical Research Network fibrosis score ≤4)
  • Known alcohol and/or other drug abuse or dependence in the past five years
  • Known history or presence of clinically significant cardiovascular, hepatic (other than NASH), gastrointestinal, metabolic other than diabetes mellitus, neurologic, pulmonary, endocrine, psychiatric, neoplastic disorder or nephrotic syndrome
  • Patients with familial hypertriglyceridemia and familial hypercholesterolemia
  • History or presence of any disease or condition known to interfere with the absorption, distribution, metabolism or excretion of drugs, including bile salt metabolism (e.g., inflammatory bowel disease; previous intestinal (ileal or colonic) operation; chronic pancreatic, celiac disease or previous vagotomy
  • Patients with heart or brain pacemaker
  • History of surgery within three months of screening which involved stent transplant or any other surgery which includes transplantation of metal devices (e.g., knee, hip etc.)
  • Weight loss of more than five percent within six months prior to randomization
  • History of bariatric surgery within five years of liver biopsy
  • Uncontrolled blood pressure
  • Women who are pregnant or breastfeeding
  • Diabetes mellitus other than Type 2 (Type 1, endocrinopathy, genetic syndromes etc.)
  • Patients with HIV infection
  • Daily alcohol intake >20 g/day for women and >30 g/day for men (on average per day), as per medical history
  • Treatment with other anti-diabetic medications: DPP-4 inhibitors unless it was stopped six months before biopsy, GLP-1 receptor agonists (such as Januvia [sitagliptin], Byetta [incretin], etc.) unless it was started at least 12 months and has remained at a stable dose more than six months prior to biopsy being taken. In case GLP-1 receptor agonist being stopped, it should be at least six months before biopsy, as per medical history
  • Metformin, fibrates, statins, insulin, sulfonylurea unless the dose has been stabilized for the last six months before screening visit
  • Treatment with valproic acid, tamoxifen, methotraxete, amiodarone, or chronic treatment with anti-cholinergic agents within 12 months before screening visit
  • Chronic antibiotic treatment (e.g., rifaximin)
  • Homeopathic and/or alternative treatments. Any treatment should be stopped during the screening period, at least 48 hours before randomization
  • Uncontrolled hypothyroidism defined as thyroid stimulating. Hormone >2 times the upper limit of normal (ULN). Thyroid dysfunction controlled for at least six months prior to screening is permitted
  • Patients with renal dysfunction eGFR<40
  • Unexplained serum creatine phosphokinase >3 x ULN. Patients with an intermittent CPK elevation may have the repeated measurement prior to randomization; a CPK retest >3 x ULN leads to exclusion

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