Non-Alcoholic Steatohepatitis (NASH), Type2 Diabetes Mellitus
Conditions
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.
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.
Interventions
BIOLOGICALOral Insulin
all patients will receive treatment regimen of a soft gel capsule of ORMD-0801.
Sponsors
Hadassah Medical Organization
Oramed, Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Mean Transient Elastography Measurement (Fibroscan) | Two timepoints: Baseline (week 0) and Week 12 | Mean Transient elasticity, measured in kPA (kilo Pascal), |
| 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 |
Countries
Israel
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oral Insulin treatment
Oral Insulin: all patients will receive treatment regimen of a soft gel capsule of ORMD-0801. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Oral Insulin |
|---|---|
| Age, Continuous | 51.8 years STANDARD_DEVIATION 11.6 |
| BMI | 32.08 Kg/M^2 STANDARD_DEVIATION 5.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment Israel | 10 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
Change in MRI-Proton Density Fat Fraction (MRI-PDFF)
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Insulin | Change in MRI-Proton Density Fat Fraction (MRI-PDFF) | MRPDFF (%) at baseline | 21.3 percentage fat in the liver | Standard Deviation 7.2 |
| Oral Insulin | Change in MRI-Proton Density Fat Fraction (MRI-PDFF) | MR PDFF (%) at Week 12 | 14.4 percentage fat in the liver | Standard Deviation 6.3 |
| Oral Insulin | Change in MRI-Proton Density Fat Fraction (MRI-PDFF) | Absolute Mean Change in MR PDFF (%) from Baseline | -6.9 percentage fat in the liver | Standard Deviation 6.8 |
p-value: 0.03125Sign test
Secondary
Mean Fibrosis Score CAP™ (FibroMax)
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Insulin | Mean Fibrosis Score CAP™ (FibroMax) | Mean Fibrosis Score at Baseline | 338.5 dB/M | Standard Deviation 15.6 |
| Oral Insulin | Mean Fibrosis Score CAP™ (FibroMax) | Mean Fibrosis Score at week 12 | 315.5 dB/M | Standard Deviation 39.6 |
Secondary
Mean Transient Elastography Measurement (Fibroscan)
Mean Transient elasticity, measured in kPA (kilo Pascal),
Time frame: Two timepoints: Baseline (week 0) and Week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Insulin | Mean Transient Elastography Measurement (Fibroscan) | Baseline | 8.6 kPa | Standard Deviation 1.5 |
| Oral Insulin | Mean Transient Elastography Measurement (Fibroscan) | Week 12 | 7.4 kPa | Standard Deviation 2.5 |