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

NCT04618744 | Completed Phase 2 Results FDA Drug

• 1 other identifier: ORA-D-N02
• Study Type: interventional
• Target: 32
• Locations: 2 countries
• Sites: 3

Brief Summary

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.

Conditions

Diabetes Mellitus, Type 2; NASH - Nonalcoholic Steatohepatitis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (20)

• Median MRPDFF at Baseline and Week 12 of Whole Liver

  Baseline and Week 12 (Visit 8)

• Percent Change From Baseline of Median MRPDFF of Whole Liver

  Baseline and Week 12 (Visit 8)

• Mean Magnetic Resonance Proton Density Fat Fraction (MRPDFF) of Whole Liver

  Baseline and Week 12

• Percent Change From Baseline in Mean Magnetic Resonance Proton Density Fat Fraction (MRPDFF) of Whole Liver

  Screening and Week 12 (Visit 8)

• Median Magnetic Resonance Proton Density Fat Fraction (MR PDFF) of Liver Segment 3

  Baseline and Week 12 (Visit 8)

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Fish oil

Other: Placebo

ORMD-0801 (Insulin) capsule 8 mg BD

EXPERIMENTAL

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

Interventions

ORMD-0801 (Insulin) capsule 8 mg BD DRUG

8 mg ORMD-0801, 1 capsule, twice a day, once in the morning and once in the evening.

Also known as: Oral Insulin

ORMD-0801 (Insulin) capsule 8 mg BD

Placebo OTHER

Matching Placebo

Also known as: Fish oil

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Oramed, Ltd.: lead
• Integrium: collaborator

Study Sites (3)

Orange County Research Center

Tustin, California, 92780, United States

Location

Hadassah Medical Center

Jerusalem, International/Other, Israel

Location

Tel Aviv Sourasky Medical Center- Ichilov Hospital

Tel Aviv, International/Other, 6423906, Israel

Location

Related Publications (6)

• 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.

  PMID: 28116801 BACKGROUND

• 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.

  PMID: 22488764 BACKGROUND

• 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.

  PMID: 20494470 BACKGROUND

• 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.

  PMID: 21623852 BACKGROUND

• 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.

  PMID: 24388431 BACKGROUND

• Ishay Y, Neutel J, Kolben Y, Gelman R, Arbib OS, Lopez O, Katchman H, Mohseni R, Kidron M, Ilan Y. Oral Insulin Alleviates Liver Fibrosis and Reduces Liver Steatosis in Patients With Metabolic Dysfunction-associated Steatohepatitis and Type 2 Diabetes: Results of Phase II Randomized, Placebo-controlled Feasibility Clinical Trial. Gastro Hep Adv. 2023 Dec 7;3(3):417-425. doi: 10.1016/j.gastha.2023.11.016. eCollection 2024.

  PMID: 39131144 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Non-alcoholic Fatty Liver Disease

Interventions

ORMD-0801; Insulin; Capsules; Fish Oils

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Fatty Liver; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Dosage Forms; Pharmaceutical Preparations; Oils; Lipids

Results Point of Contact

• Title: Chief Scientific Officer
• Organization: Oramed, Ltd.

miriam@oramed.com

+97225660001

Study Officials

• Miriam Kidron, Ph.D.

  Oramed, Ltd.

  STUDY DIRECTOR

• Joel M Neutel, M. D.

  Integrium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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 Record Dates

• First Submitted: November 1, 2020
• First Posted: November 6, 2020
• Study Start: November 24, 2020
• Primary Completion: June 27, 2022
• Study Completion: June 27, 2022
• Last Updated: August 7, 2024
• Results First Posted: August 7, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); IL (2)