A Study to Assess the Safety and Efficacy of Oral Insulin in T2DM Patients With Nonalcoholic Steatohepatitis (NASH)

This is a double-blind, randomized, placebo-controlled, multi-center study using the oral ORMD-0801 insulin formulation in patients with NASH and confirmed type 2 DM. The study will consist of a Screening Phase, Placebo Run-in Phase, Treatment Phase and an End-of-Study Phase. Approximately 36 subjects will be randomized in a 2:1 ratio to receive either 8 mg ORMD-0801, 1 capsule twice a day (once in the morning approximately 30 to 45 minutes prior to breakfast and no later than 10 AM, and once at night between 8 PM to Midnight and no sooner than 1 hour after dinner) or matching placebo.

Inclusion criteria

• Male or female aged 18-70 years.
• BMI ≥25
• 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 > 6.5%28 or on treatment with metformin only or metformin in addition to no more than two of the following medications sulfonylurea, DPP-4 inhibitors, GLP-1 receptor agonists, Thiazolidinediones (TZDs)
• Diagnosis of NAFLD by non-invasive determination of hepatic steatosis grade S1, defined as hepatic steatosis>8% by MRI- PDFF and CAP FibroScan ≥ 238 dB/m.
• Liver enzyme abnormalities: ULN≤5 times.
• Fibrosis score 21≤F≤3 as defined by FibroScan measurement (Liver stiffness measurement, LSM) of 6 ≤ LSM ≤ 12 kPa.
• Signature of the written informed consent.
• Negative urine serum pregnancy test at Screening study entry for females of childbearing potential (WCBP).
• WCBP must have a negative urine pregnancy test result prior to the start of the run-in period and initiation if 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 (double barrier method), one of which must be an acceptable barrier method from the time of screening to the last dosing study visit (22 weeks). Barrier methods of contraception include male condoms plus spermicide, diaphragm with spermicide plus male condom, cervical cap with spermicide plus male condom, or oral contraceptives. Acceptable methods of birth control include abstinence, oral contraceptives, surgical sterilization, vasectomy, the contraceptive patch, and the contraceptive ring. If a subject is not usually sexually active but becomes active, he or his partner should use medically accepted forms of contraception. Sperm donations will not be allowed for the duration of the study and for 90 days after the last dose of study drug.
• 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 (FSH Level > 40), b) who are surgically menopausal (surgical sterility defined by tubal occlusion, bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• For hypertensive patients, hypertension must be controlled by a stable dose of anti-hypertensive medication for at least 2 months prior to screening (and the stable dose can be maintained throughout the study) with BP < 150/<95 mmHg
• Patients previously treated with vitamin E (>400IU/day), Polyunsaturated fatty acid (>2g/day) or Ursodeoxycholic acid fish oil can be included if drugs are stopped at least 3 months prior to enrolment and up to the end of the study.
• Glycaemia must be controlled (Glycosylated Hemoglobin A1C ≤8.5%) 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-1 antitrypsin deficiency, alcohol liver disease, drug-induced liver disease) at the time of enrolment.
• ALT or AST > 5 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 (264.6 lbs.)
• 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 enrolment.
• History of bariatric surgery.
• Uncontrolled blood pressure BP ≥150/≥95.
• Non-type 2 DM (type 1, endocrinopathy, genetic syndromes etc.).
• Patients with HIV.
• Daily alcohol intake >20 g/day (2 units/day) for women and >30 g/day (3 units/day) for men.
• Treatment with anti-diabetic medications other than metformin and more than two of the following medications sulfonylurea, DPP-4 inhibitors, GLP-1 receptor agonists, TZDs
• Metformin, fibrates, statins, not provided on a stable dose in the last 6 months.
• Patients who are treated with valproic acid, Tamoxifen, methotrexate, amiodarone.
• Chronic treatment with antibiotics (e.g. Rifaximin).
• Homeopathic and/or Alternative treatments. Any treatment must be stopped before the screening period.
• 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.
• Patients with renal dysfunction: eGFR< 40 ml/min.
• Unexplained serum creatinine phosphokinase (CPK) >3X the upper limit of normal (ULN). Patients with a reason for CPK elevation may have the measurement repeated prior to enrolment; a CPK retest > 3X ULN leads to exclusion.
• Subjects meeting criteria for contraindication for MRI - including the following:

i. History of severe claustrophobia impacting the ability to perform MRI during the study, even despite mild sedation/treatment with as anxiolytic.

ii. Subjects with metal implants, devices, paramagnetic objects contained within the body, and excessive or metal-containing tattoos.

iii. Subjects unable to lie still within the environment of the MRI scanner or maintain a breath-hold for the required period to acquire images, even despite mild sedation/treatment with an anxiolytic.

• The subject participated in a clinical research study involving a new chemical entity within 4 weeks of study entry.
• Known allergy to soy.