Safety, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Multiple Oral Bedtime Doses of ORMD-0801 in Adult Patients With Type 2 Diabetes Mellitus (T2DM)

This is a single-center, Phase II(a), randomized, double-blind, placebo-controlled, parallel group, inpatient study preceded by a 5-day single-blind outpatient placebo run-in period.

Inclusion criteria

• Male or female patients, age 20 to 70 years, inclusive with T2DM;
• At randomization, patients are treated for diabetes by diet and exercise, or by diet, exercise and metformin (>1000 mg/day; any type and regimen). Patients on a stable regimen of metformin (defined as the same metformin dose and type) for at least 6 weeks prior to entering the placebo run-in period. Other anti-diabetic agents not in use for the 6 weeks prior to entering the placebo run-in period;
• 25 kg/m2 ≤ BMI ≤ 40 kg/m2
• 6.5% ≤ HbA1c ≤ 10.5%, prior to randomization)
• Fasting plasma glucose ≥ 126 mg/dL (8.3 mmo1/L) prior to randomization;
• No tobacco or nicotine use within 10 wks prior to screening;
• Females of child-bearing potential must have a negative serum pregnancy test result at screening and a negative urine pregnancy test at Visit 3. Females of non-childbearing potential are defined as postmenopausal who:

• had more than 24 months since last menstrual cycle with menopausal levels of FSH;
• age > 55 years old; or
• are surgically menopausal.

Exclusion criteria

• Presence of any clinically significant endocrine disease according to the PI;
• Clinical diagnosis of T1DM;
• Fasting plasma glucose > 260 mg/dL at the end of washout/stabilization/run-in periods;
• Evidence of unawareness of hypoglycemia, a documented plasma glucose ≤ 50 mg/dL in the absence of symptoms of hypoglycemia;
• Presence of any clinically significant condition that might interfere with the evaluation of study medication;
• Presence or history of cancer within the past 5 yrs. with the exception of adequately-treated localized basal cell skin cancer or in situ uterine cervical cancer;
• Laboratory abnormalities at screening:

• C-peptide < 1.0 ng/mL;
• Positive pregnancy test in females of childbearing potential (at screening and start of run-in period);
• Abnormal TSH levels > 1.5 x the upper limit of normal;
• Positive test for hepatitis B surface antigen and/or hepatitis C antibody;
• Positive test for HIV;
• Any relevant abnormality interfering with the efficacy or the safety assessments during study drug administration;
• Use of the following medications

• History of use of insulin for no more than 1 wk in the last 6 mos and none in the last 6 wks prior to randomization;
• History of use of aprotinin at any time prior to the screening visit;
• Administration of anti-diabetic drugs other than metformin within 6 wks prior to run-in period;
• Administration of thiazolidinedione treatment within 3 months prior to randomization;
• Administration of thyroid preparations or thyroxine (except in patients on stable replacement therapy) within 6 weeks prior to screening visit;
• Administration of systemic long-acting corticosteroids within two months or prolonged use of other systemic corticosteroids or inhaled corticosteroids within 30 days prior to screening visit;
• Use of medications known to modify glucose metabolism or to decrease the ability to recover from hypoglycemia such as oral, parenteral, and inhaled steroids, beta blockers (with the exception of beta blocker ophthalmic solutions for glaucoma or ocular hypertension), and immunosuppressive or immunomodulating agents.
• History of severe or multiple allergies;
• History of tobacco or nicotine use within 10 wks prior to screening
• Patient is on a weight loss program and is not in the maintenance phase, or patient that started weight loss medication within 8 wks prior to screening;
• Pregnancy or breast-feeding;
• Patient has a screening visit systolic blood pressure of ≥165 mm Hg or diastolic blood pressure of ≥100 mm Hg. Patients will be allowed to take a BP rescue medication as long as it does not affect glucose metabolism (e.g., diuretics) or sensation of hypoglycemia (e.g., beta-blockers);
• Patient is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence;
• Elevated liver enzymes ALT, AST, alkaline phosphatase) > 2 x the upper limit of normal at screening;
• Very high triglyceride level (>600 mg/dL) at screening;
• ECG abnormality at screening or CV. Clinically significant CV will include

• history of stroke, transient ischemic attack, or MCI within 6 months prior to screening;
• history of or currently have NYHA Class II-IV heart failure prior to screening; or
• uncontrolled hypertension defined as BP ≥180 mmHg (systolic) or ≥110 mmHG (diastolic) at screening or at Visit 2;
• One or more contraindications to metformin;
• History of gastrointestinal disorders with the potential to interfere with drug absorption;

At the Principal Investigator's discretion, any condition or other factor that is deemed unsuitable for patient enrollment into the study