A Pilot Study to Assess the Safety of Oral Insulin in Patients With Nonalcolholic Steatohepatitis (NASH)

Study Overview
=================
Brief 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.

Detailed Description
-----------------
This exploratory study will first enroll 10 patients with NASH and type 2 DM, to evaluate the safety of oral insulin and to measure the change in liver fat content. At the completion of their 4-week follow-up period, results will be presented to the Helsinki Committee. Following approval, an additional 20 patients will be enrolled. The size of the study population was determined by the investigator (with literature review) to be sufficient to show trends of reducing liver fat content by analysis of MRI PDFF (MRI-Proton Density Fat Fraction) images, the FibroMax™ Test and Fibroscan® including Controlled Attenuation Parameter (CAP™). CAP™ is a measure of the ultrasound attenuation to quantify steatosis in the liver.

Official Title
-----------------
An Open-Label Pilot Study to Assess the Safety, Pharmacokinetics, Pharmacodynamics and Potential of Oral Insulin to Reduce Liver Fat Content and Fibrosis in Patients With Nonalcolholic Steatohepatitis (NASH)

Conditions
-----------------
Non-Alcoholic Steatohepatitis (NASH), Type2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Biological: Oral Insulin


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Insulin<br>treatment | Biological: Oral Insulin<br>* all patients will receive treatment regimen of a soft gel capsule of ORMD-0801.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MRI-Proton Density Fat Fraction (MRI-PDFF) | Absolute Change in MRI-Proton Density Fat Fraction (expressed as percent fat in the liver) from baseline to week 12 | Two timepoints: Baseline (week 0) and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Transient Elastography Measurement (Fibroscan) | Mean Transient elasticity, measured in kPA (kilo Pascal), | Two timepoints: Baseline (week 0) and Week 12 | 
| Mean Fibrosis Score CAP™ (FibroMax) | Mean fibrosis score (severity scale of liver fibrosis) measured at baseline and week 12. Fibrosis Score CAP measures the amount of steatosis (fatty change) in the liver. The CAP score is measured in decibels per meter (dB/m). It ranges from 100 to 400 dB/m with higher values indicating more fatty change | Two timepoints: Baseline (week 0) and Week 12 |