A Pilot Study to Assess the Safety of Oral Insulin in Patients With Nonalcolholic Steatohepatitis (NASH)
Condition: Non-Alcoholic Steatohepatitis (NASH); Type2 Diabetes Mellitus
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2
Intervention: Oral Insulin
Intervention description: all patients will receive treatment regimen of a soft gel capsule of ORMD-0801.
Intervention MeSH terms: Insulin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      This is an open, pilot study using the oral ORMD-0801 insulin formulation in patients with
      NASH and confirmed type 2 DM or pre-diabetes. The study will consist of a Screening, placebo
      run-in, treatment phase and end-of-study phase.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Known type 2 DM according to American Diabetic Association (one of the three needed):
             Fasting Plasma Glucose ≥126 mg/dl or 2h postprandial (PG) following 75g OGTT ≥ 200
             mg/dl or HbA1C > 5.7% or on treatment with metformin

          -  Abdominal ultrasound (US) proven fatty liver performed within 6 months before
             randomization, confirmed by central US.

          -  Fat concentration in the liver of S2 (moderate steatosis, 6-32% hepatocytes with
             steatosis) or more as measured by Fibromax.

          -  Signature of the written informed consent.

          -  Negative pregnancy test at study entry for females of child bearing potential.

          -  Females must have a negative urine pregnancy test result at screening, prior to the
             start of the run-in period, and at initiation of active dosing. A negative urine and
             serum pregnancy test must be obtained prior to active dosing. Males and females of
             childbearing potential must use two methods of contraception.

          -  Females of non-childbearing potential are defined as postmenopausal who a) had more
             than 24 months since last menstrual cycle with menopausal levels of FSH, b) who are
             surgically menopausal.

          -  For hypertensive patients, hypertension must be controlled by stable dose of
             anti-hypertensive medication for at least 2 months prior to screening with BP <
             150/<95 mmHg

          -  Patients previously treated with vitamin E (>400IU/day).

          -  Glycaemia must be controlled (Glycosylated Hemoglobin A1C ≤9%) while any HbA1C
             increment should not exceed 1% during 6 months prior to enrolment).

        Exclusion Criteria:

          -  Patients with active (acute or chronic) liver disease other than NASH (e.g. viral
             hepatitis, genetic hemochromatosis, Wilson disease, alpha 1antitripsin deficiency,
             alcohol liver disease, drug induced liver disease) at the time of randomization.

          -  ALT or AST ≥ 2 times ULN

          -  Abnormal synthetic liver function (serum albumin ≤3.5gm%, INR >1.3).

          -  Known alcohol and/or any other drug abuse or dependence in the last five years.

          -  Weight >120 Kg

          -  Known history or presence of clinically significant cardiovascular, gastrointestinal,
             metabolic (other than diabetes mellitus), neurologic, pulmonary, endocrine,
             psychiatric, neoplastic disorder or nephrotic syndrome.

          -  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.

          -  Weight loss of more than 5% within 6 months prior to randomization.

          -  History of bariatric surgery.

          -  Uncontrolled blood pressure BP ≥150/95.

          -  Non type 2 DM (type I, endocrinopathy, genetic syndromes etc).

          -  Patients with HIV.

          -  Daily alcohol intake >20 g/day for women and >30 g/day for men.

          -  Treatment anti-diabetic medications other than metformin, such as DPP-4 inhibitors,
             GLP-1 receptor agonists, TZDs, etc.

          -  Metformin, Fibrates, Statins, not provided on a stable dose in the last 6 months.

          -  Patients who are treated with Valproic acid, Tamoxifen, Methotrexate, Amiodaron.

          -  Chronic treatment with antibiotics (e.g. Rifaximin).

          -  Homeopathic and/or Alternative treatments.

          -  Uncontrolled hypothyroidism defined as Thyroid Stimulating Hormone >2X the upper limit
             of normal (UNLN).

          -  Patients with renal dysfunction: eGFR< 40 ml/min.

          -  Unexplained serum creatinine phosphokinase