A Study to Evaluate the Efficacy and Safety of ORMD-0801 (Oral Insulin) in Patients With Type 2 Diabetes Mellitus

This is a four-way (Participant, Care Provider, Investigator, Outcomes Assessor) masked (blinded) study designed to explore the efficacy of ORMD-0801 when given in different regimens across a dose range for up to 12 weeks in subjects with type 2 diabetes mellitus (T2DM).

This study is designed to explore the efficacy of ORMD-0801 when given in different regimens across a dose range for up to 12 weeks in subjects with type 2 diabetes mellitus (T2DM). There are two cohorts in this study. Approximately 360 subjects with T2DM will initially undergo a 2-week, single-blind placebo run-in period (Visits 1 and 2), followed by a 12-week treatment period (Visits 3 through 9). Cohort A will enroll 285 subjects; Cohort B will enroll 75 subjects

For 265 of the 285 subjects of Cohort A, the total 12-week treatment period will include a Part 1"dose escalation" interval (2 weeks, Visits 3 and 4) and a Part 2 stable dose "maintenance" interval (10 weeks, Visits 5 through 9).

In addition, per FDA request, the remaining 20 subjects (of the cohort total of 285 enrolled subjects) will receive excipient-matched placebo in a non-randomized single-blind fashion, TID (3 times per day), according to the same schedule as described above.

For Cohort B (75 of the 360 total subjects), the total 12-week treatment period will include a stable dosing period for both Part 1 (2 weeks, Visits 3 and 4) and Part 2 (10 weeks, Visits 5 through 9).

Cohort A data will be analyzed after Cohort A data collection has been completed (last subject for Cohort A screened on 7 May 2019). Estimated completion for Cohort A is October 2019. Cohort B data will be analyzed following the release of results from Cohort A.

Eligibility Criteria:
Inclusion Criteria:

* Male and female subjects aged 18 and older.
* Established diagnosis of T2DM for at least 6 months prior to Screening, with an HbA1C (glycated hemoglobin) ≥ 7.5%.
* Stable dose of metformin (at least 1500 mg or maximally tolerated dose)/oral antidiabetic (OAD) for a period of at least 3 months prior to screening.
* Taking metformin only or metformin in addition to no more than two of the following: DPP-4 (DiPeptidyl Peptidase-4), SGLT-2 (Sodium-GLucose coTransporter-2), or TZD (Thiazolidinediones).
* Body mass index (BMI) of up to 40 kg/m2 at Screening and stable weight, with no more than 5 kg gain or loss in the 3 months prior to Screening.
* Renal function - eGFR (estimated glomerular filtration rate) \> 30 ml/min/1.73 m2
* Females of childbearing potential must have a negative serum pregnancy test result at Screening.

Exclusion Criteria:

* Subjects with insulin-dependent diabetes

  1. has a history of type 1 diabetes mellitus or a history of ketoacidosis, or subject is assessed by the investigator as possibly having type 1 diabetes mellitus confirmed by a C-peptide \<0.7 ng/mL (0.23 nmol/L).
  2. has a history of other specific types of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ transplant).
* Treatment with glucosidase inhibitor, insulin secretagogues (other than sulfonylureas), glucagon-like peptide 1 (GLP-1) agonists within 3 months prior to Visit 1.
* History of any basal, pre-mix or prandial insulin (greater than 7 days) within 6 months prior to Screening.
* History of \>2 episodes of severe hypoglycemia within 6 months prior to Screening.
* History of hypoglycemic unawareness (episodes of severe hypoglycemia with seizure or requiring third-party intervention or documented low blood glucose without associated autonomic symptoms)
* Subjects with the following secondary complications of diabetes:

  1. Active proliferative retinopathy as confirmed by a dilated ophthalmoscopy/retinal photography examination performed (by a qualified person as per the country legislation) within 6 months prior to Screening.
  2. Renal dysfunction: eGFR \< 30 ml/min/1.73 m2
  3. History of proliferative retinopathy or severe form of neuropathy or cardiac autonomic neuropathy (CAN)
  4. Uncontrolled or untreated severe hypertension defined as systolic blood pressure above or equal to 180 mmHg and/or diastolic blood pressure above or equal to 120 mmHg
  5. Presence of unstable angina or myocardial infarction within 6 months prior to Screening, Grade 3 or 4 congestive heart failure (CHF) according to the New York Heart Association (NYHA) criteria, valvular heart disease, cardiac arrhythmia requiring treatment, pulmonary hypertension, cardiac surgery, history/occurrence of coronary angioplasty and/or stroke or transient ischemic attack (TIA) within 6 months prior to Screening.
* Subjects with psychiatric disorders which, per investigator judgment may have an impact on the safety of the subject or interfere with the subject's participation or compliance in the study.
* Subjects who needed (in the last 12 months) or may require systemic (oral, intravenous, intramuscular) glucocorticoid therapy for more than 2 weeks during the study period.
* 9. Laboratory abnormalities at Screening include:

  1. C-peptide \< 1.0 ng/mL
  2. Abnormal serum thyrotropin (TSH) levels below the lower limit of normal or \>1.5X the upper limit of normal
  3. Elevated liver enzymes (alanine transaminase (ALT), alanine aminotransferase (AST), alkaline phosphatase) \>2X the upper limit of normal.
  4. Very high triglyceride levels (\>600 mg/dL); a single repeat test is allowable.
  5. Any relevant abnormality that would interfere with the efficacy or the safety assessments during the study treatment administration.
* Positive history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic hepatitis B or C, primary biliary cirrhosis, or active symptomatic gallbladder disease.
* Positive history of HIV.
* Use of the following medications:

  1. History of any basal, pre-mix or prandial insulin (greater than 7 days) within 6 months prior to Screening.
  2. Administration of thyroid preparations or thyroxine (except in subjects on stable replacement therapy) within 6 weeks prior to Screening.
  3. Administration of systemic long-acting corticosteroids within two months or prolonged use (more than one week) of other systemic corticosteroids or inhaled corticosteroids (if daily dosage is \> 1,000 μg equivalent beclomethasone) within 30 days prior to Screening. Intra-articular and/or topical corticosteroids are not considered systemic.
  4. Use of medications known to modify glucose metabolism or to decrease the ability to recover from hypoglycemia such as oral, parenteral, and inhaled steroids (as discussed above), and immunosuppressive or immunomodulating agents.
* Known allergy to soy.
* Subject is on a weight loss program and is not in the maintenance phase or subject has started weight loss medication (e.g., orlistat or liraglutide), within 8 weeks prior to Screening.
* Subject has had bariatric surgery.
* Subject is pregnant or breastfeeding.
* Subject is a user of recreational or illicit drugs or has had a recent history (within 1 year of Screening) of drug or alcohol abuse or dependence. (Note: Alcohol abuse includes heavy alcohol intake as defined by \>3 drinks per day or \>14 drinks per week, or binge drinking) at Screening. Occasional intermittent use of cannabinoid products will be allowed provided that no cannabinoid products have been used during the 1 week prior to each visit.
* One or more contraindications to metformin as per local label.
* History of gastrointestinal disorders (e.g. hypochlorhydria) with the potential to interfere with drug absorption.
* At the Principal Investigator's discretion, any condition or other factors that are deemed unsuitable for subject enrollment into the study.