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

A Double-Blind, Randomized, Placebo-controlled, Multi-center Study to Assess the Safety and Efficacy of Oral Insulin to Reduce Liver Fat Content in Type 2 Diabetes 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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; NASH - Nonalcoholic Steatohepatitis
• Intervention / Treatment: Other: Placebo; Drug: ORMD-0801 (Insulin) capsule 8 mg BD

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• Israel
  • International/Other
    • Jerusalem, International/Other, Israel
      • Hadassah Medical Center
    • Tel Aviv, International/Other, Israel, 6423906
      • Tel Aviv Sourasky Medical Center- Ichilov Hospital
• United States
  • California
    • Tustin, California, United States, 92780
      • Orange County Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Fish oil	Other: Placebo; Matching Placebo; Other Names: Fish oil
Experimental: ORMD-0801 (Insulin) capsule 8 mg BD; ORMD-0801 (insulin) capsule Dose: 8 mg BD Dosage Regimen: 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) Mode of Administration: Oral	Drug: ORMD-0801 (Insulin) capsule 8 mg BD; 8 mg ORMD-0801, 1 capsule, twice a day, once in the morning and once in the evening.; Other Names: Oral Insulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Treatment-Emergent Adverse Events	The Number of Treatment-Emergent Adverse Events (TEAE) according to CTCAE version 4.03. A TEAE is an adverse event for which the start date is on or after the date that the treatment began.	Screening through Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median MRPDFF at Baseline and Week 12 of Whole Liver	Median MRPDFF at Baseline and Week 12 of Whole Liver. Delineation by a central radiologist of the whole liver in the slice with the largest liver cross-section. The Liver was subdivided into 8 sections according to the Coinaud liver segmentation for MRI.	Baseline and Week 12 (Visit 8)
Percent Change From Baseline of Median MRPDFF of Whole Liver	The percent change in MR PDFF from baseline to Week 12 of Whole Liver	Baseline and Week 12 (Visit 8)
Mean Magnetic Resonance Proton Density Fat Fraction (MRPDFF) of Whole Liver	Mean Magnetic Resonance Proton Density Fat Fraction (MRPDFF) of Whole Liver at Baseline and Week12. The Whole liver was delineated by a central radiologist. The liver was subdivided into 8 sections according to the Coinaud liver segmentation for MRI.	Baseline and Week 12
Percent Change From Baseline in Mean Magnetic Resonance Proton Density Fat Fraction (MRPDFF) of Whole Liver	The percent change from basline in liver fat content as measured by the mean MRI Proton density Fat Fraction (MR PDFF) at baseline and at week 12 of Whole Liver	Screening and Week 12 (Visit 8)
Median Magnetic Resonance Proton Density Fat Fraction (MR PDFF) of Liver Segment 3	Median MRPDFF (percentage fat in the liver) of liver segment 3 as measured by MRI Proton Density Fat Fraction at baseline and at week 12. Delineation by a central radiologist of the Liver Segment 3 in the slice with the largest Liver Segment 3 cross-section.	Baseline and Week 12 (Visit 8)
Percent Change From Baseline of Median MRPDFF of Liver Segment 3	Percent Change from Baseline Median MRPDFF of Liver Segment measured at baseline and Week 12 (Visit 8)	Baseline and Week 12 (Visit 8)
Mean MRPDFF of Liver Segment 3	Mean MRPDFF of Liver Segment measured at baseline and Week 12	Baseline and Week 12 (Visit 8)
Percent Change of Mean MRPDFF of Liver Segment 3	Percent change from baseline of mean MR PDFF measurement of liver segment 3 at baseline and week 12	Baseline and Week 12 (Visit 8)
Median MR PDFF of Liver Segment 6	Median Magnetic Resonance Proton Density Fat Fraction of Liver Segment 6 measured at baseline and at week 12 (Visit 8). Delineation by a central radiologist of Liver Segment 6 in the slice with the largest Liver Segment 6 cross-section.	Screening and Week 12 (Visit 8)
Percent Change From Baseline of Median MR PDFF of Liver Segment 6	Percent Change from Baseline of Median Magnetic Resonance Proton Density Fat Fraction of Liver Segment 6 measured at baseline and at week 12	Screening and Week 12 (Visit 8)
Mean MR PDFF of Liver Segment 6	Mean Magnetic Resonance Proton Density Fat Fraction of Liver Segment 6 measured at baseline and at week 12 (Visit 8)	Screening and Week 12 (Visit 8)
Percent Change From Baseline of Mean MR PDFF of Liver Segment 6	Percent Change from Baseline Mean Magnetic Resonance Proton Density Fat Fraction of Liver Segment 6 measured at baseline and at week 12 (Visit 8)	Screening and Week 12 (Visit 8)
Median MRPDFF of Liver Segment 8	Median MRPDFF of Liver Segment 8 measured at baseline and Week 12 (Visit 8)	Baseline and Week 12 (Visit 8)
Percent Change in Median MRPDFF of Liver Segment 8	Percent change from baseline in median MRPDFF of Liver segment 8 measured at baseline and week 12 (Visit 8).	Baseline and Week 12 (Visit 8)
Mean MRPDFF of Liver Segment 8	Liver fat percentage of liver segment 8 as measured by MRI Proton Density Fat Fraction (MR PDFF) at baseline and at week 12 (Visit 8). Delineation by a central radiologist of Liver Segment 8 in the slice with the largest Liver Segment 8 cross-section.	Baseline and Week 12 (Visit 8)
Percent Change From Baseline in Mean MRPDFF of Liver Segment 8	Percent change from baseline in MRPDFF of liver segment 8 at baseline and at week 12 (Visit 8)	Baseline and Week 12 (Visit 8)
Liver Steatosis	Liver steatosis measured by FibroScan® at baseline and at week 12 (Visit 8), in units of decibels per meter (dB/M)	Baseline and Week 12 (Visit 8)
Change in Liver Steatosis From Baseline	Change in Liver steatosis from baseline measured by FibroScan® at baseline and at week 12 (Visit 8), in units of decibels per meter (dB/M)	Baseline and Week 12 (Visit 8)
Liver Fibrosis	Liver fibrosis measured by FibroScan® at baseline and at week 12 (Visit 8), in units of kilo Pascals (kPa).	Baseline and Week 12 (Visit 8)
Change From Baseline of Liver Fibrosis	The change from baseline in liver fibrosis measured by FibroScan® at baseline and at week 12 (Visit 8), in units of kilo Pascals (kPa).	Baseline and Week 12 (Visit 8)

Collaborators and Investigators

• Sponsor: Oramed, Ltd.
• Collaborators: Integrium
• Investigators: Principal Investigator: Joel M Neutel, M. D., Integrium; Study Director: Miriam Kidron, Ph.D., Oramed, Ltd.

Publications and helpful links

General Publications

• Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012 Jun;55(6):2005-23. doi: 10.1002/hep.25762. No abstract available.
• Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011 Aug;34(3):274-85. doi: 10.1111/j.1365-2036.2011.04724.x. Epub 2011 May 30.
• Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010 Aug;53(2):372-84. doi: 10.1016/j.jhep.2010.04.008. Epub 2010 May 7. No abstract available.
• Lin SC, Heba E, Bettencourt R, Lin GY, Valasek MA, Lunde O, Hamilton G, Sirlin CB, Loomba R. Assessment of treatment response in non-alcoholic steatohepatitis using advanced magnetic resonance imaging. Aliment Pharmacol Ther. 2017 Mar;45(6):844-854. doi: 10.1111/apt.13951. Epub 2017 Jan 24.
• Germain T, Favelier S, Cercueil JP, Denys A, Krause D, Guiu B. Liver segmentation: practical tips. Diagn Interv Imaging. 2014 Nov;95(11):1003-16. doi: 10.1016/j.diii.2013.11.004. Epub 2013 Dec 30.

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2020
• Primary Completion (Actual): June 27, 2022
• Study Completion (Actual): June 27, 2022

Study Registration Dates

• First Submitted: November 1, 2020
• First Submitted That Met QC Criteria: November 1, 2020
• First Posted (Actual): November 6, 2020

Study Record Updates

• Last Update Posted (Actual): August 7, 2024
• Last Update Submitted That Met QC Criteria: July 11, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Liver Diseases; Diabetes Mellitus, Type 2; Fatty Liver; Non-alcoholic Fatty Liver Disease; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: ORA-D-N02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No