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

• Sponsor: Oramed, Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02653300
• Collaborator: Hadassah Medical Organization (Other)
• Enrollment: 10
• Location: 1
• Arm: 1
• Actual Duration (Months): 18.4
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Non-Alcoholic Steatohepatitis (NASH); Type2 Diabetes Mellitus	Biological: Oral Insulin	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Sep 20, 2018
• Actual Primary Completion Date: Mar 1, 2020
• Actual Study Completion Date: Apr 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oral Insulin treatment	Biological: Oral Insulin; all patients will receive treatment regimen of a soft gel capsule of ORMD-0801.

Outcome Measures

Primary Outcome Measures

1. Change in MRI-Proton Density Fat Fraction (MRI-PDFF) [Two timepoints: Baseline (week 0) and Week 12]

   Absolute Change in MRI-Proton Density Fat Fraction (expressed as percent fat in the liver) from baseline to week 12

Secondary Outcome Measures

1. Mean Transient Elastography Measurement (Fibroscan) [Two timepoints: Baseline (week 0) and Week 12]

   Mean Transient elasticity, measured in kPA (kilo Pascal),

2. Mean Fibrosis Score CAP™ (FibroMax) [Two timepoints: Baseline (week 0) and Week 12]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hadassah Medical Center	Jerusalem		Israel

Sponsors and Collaborators

• Oramed, Ltd.
• Hadassah Medical Organization

Investigators

• Principal Investigator: Rifaat Safadi, M.D., Hadassah Medical Organization

Study Documents (Full-Text)

• Study Protocol: Clinical Protocol ORA-D N01 - Jan 7, 2018

More Information

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.
• 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.
• 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.
• 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. Review.

• Responsible Party: Oramed, Ltd.
• ClinicalTrials.gov Identifier: NCT02653300
• Other Study ID Numbers: ORA-D-N01
• First Posted: Jan 12, 2016
• Last Update Posted: Sep 23, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Insulin

Study Results

Participant Flow

Arm/Group Title	Oral Insulin
Arm/Group Description	treatment Oral Insulin: all patients will receive treatment regimen of a soft gel capsule of ORMD-0801.
Period Title: Overall Study
STARTED	10
COMPLETED	8
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Oral Insulin
Arm/Group Description	treatment Oral Insulin: all patients will receive treatment regimen of a soft gel capsule of ORMD-0801.
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.8 (11.6)
Sex: Female, Male (Count of Participants)
Female	3 30%
Male	7 70%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	10 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Israel	10 100%
BMI (Kg/M^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg/M^2]	32.08 (5.2)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Insulin
Arm/Group Description	treatment Oral Insulin: all patients will receive treatment regimen of a soft gel capsule of ORMD-0801.
Measure Participants	8
MRPDFF (%) at baseline	21.3 (7.2)
MR PDFF (%) at Week 12	14.4 (6.3)
Absolute Mean Change in MR PDFF (%) from Baseline	-6.9 (6.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Insulin
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03125
	Comments
	Method	Sign test
	Comments

2. Secondary Outcome

Title	Mean Transient Elastography Measurement (Fibroscan)
Description	Mean Transient elasticity, measured in kPA (kilo Pascal),
Time Frame	Two timepoints: Baseline (week 0) and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Insulin
Arm/Group Description	treatment Oral Insulin: all patients will receive treatment regimen of a soft gel capsule of ORMD-0801.
Measure Participants	8
Baseline	8.6 (1.5)
Week 12	7.4 (2.5)

3. Secondary Outcome

Title	Mean Fibrosis Score CAP™ (FibroMax)
Description	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
Time Frame	Two timepoints: Baseline (week 0) and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Insulin
Arm/Group Description	treatment Oral Insulin: all patients will receive treatment regimen of a soft gel capsule of ORMD-0801.
Measure Participants	8
Mean Fibrosis Score at Baseline	338.5 (15.6)
Mean Fibrosis Score at week 12	315.5 (39.6)

Adverse Events

Time Frame	twelve weeks (Baseline to 12 weeks)
Arm/Group Title	Oral Insulin
Arm/Group Description	treatment Oral Insulin: all patients will receive treatment regimen of a soft gel capsule of ORMD-0801.
All Cause Mortality
	Oral Insulin
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Serious Adverse Events
	Oral Insulin
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Other (Not Including Serious) Adverse Events
	Oral Insulin
	Affected / at Risk (%)	# Events
Total	0/8 (0%)

Limitations/Caveats

This is a pilot study with ten subjects enrolled, and eight subjects analyzed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.