A Study of Oral Insulin to Reduce Liver Fat Content in Type 2 Diabetes Patients With Nonalcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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A Study to Assess the Safety and Potential of Oral Insulin to Reduce Liver Fat Content in Type 2 Diabetes Patients with Nonalcoholic Steatohepatitis (NASH)

Detailed Description
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An Open-Label Multi-Center Study to Assess the Safety and Potential of Oral Insulin to Reduce Liver Fat Content in Type 2 Diabetes Patients with Nonalcoholic Steatohepatitis (NASH)

Official Title
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An Open-Label Multi-Center Study to Assess the Safety and Potential of Oral Insulin to Reduce Liver Fat Content in Type 2 Diabetes Patients With Nonalcoholic Steatohepatitis (NASH)

Conditions
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Nonalcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: ORMD-0801 QD
* Drug: ORMD-0801 BD


Participation Criteria
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Eligibility Criteria
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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 urineserum pregnancy test at Screening study entry for women of childbearing potential (WCBP). Women of childbearing potential (WCBP) must have a negative urine pregnancy test result prior to the start of the run-in period and at. initiation of 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 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). Patients who are willing to participate in the study, have to have their own self-monitoring blood glucose devices. 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: History of severe claustrophobia impacting ability to perform MRI during the study, even despite mild sedation/treatment with as anxiolytic. Subjects with metal implants, devices, paramagnetic objects contained within the body and excessive or metal-containing tattoos. 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. Subject participated in a clinical research study involving a new chemical entity within 4 weeks of study entry. Known allergy to soy.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: This is an open, multi-center study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: ORMD-0801 QD<br>8 mg QD, daily, in the morning | Drug: ORMD-0801 QD<br>* 8 mg, QD<br>* Other names: Oral Insulin;|
| Other: ORMD-0801 BD<br>8 mg BD, daily in the morning and in the evening | Drug: ORMD-0801 BD<br>* 8 mg, BD<br>* Other names: Oral Insulin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events. | Safety of Oral Insulin will be measured by the number of treatment-related adverse events according to CTCAE version 5.0 | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in liver fat content | The percent change in liver fat content measured by MRI-Proton Density Fat Fraction from baseline to week 12 | Screening(Baseline) and Week 12 | 
| Percent change in liver fibrosis | Percent change in liver fibrosis as measured by FibroScan Elasticity in units of kilo Pascals (kPa) | Screening, Week 0, and Week 12 | 
| Percent change in liver steatosis | Percent change in liver steatosis as measured by FibroScan Controlled Attenuation Parameter (CAP) in units of dB/meter | Screening, Week 0, and Week 12 |