A Study to Evaluate the Efficacy and Safety of ORMD-0801 (Oral Insulin) in Patients With Type 2 Diabetes Mellitus
Condition: T2DM (Type 2 Diabetes Mellitus)
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Cohort A: ORMD-0801; Placebo oral capsule; Cohort B: ORMD-0801
Intervention description: Part 1 In the first two weeks of active treatment (Part 1) subjects will receive double-blind therapy according to their randomized regimen (placebo or ORMD-0801) to be taken QHS, BID or TID. Subjects will undergo a step-wise dose escalation from a starting dose of 16 mg (Visit 3), to 24 mg (Visit 4), to a top dose of 32 mg (Visit 5 onward). Subjects will then enter Part 2.
Part 2:
During Part 2, subjects will remain on fixed doses of ORMD-0801 (or matched placebo) for 10 weeks. Doses will not be adjusted unless clinically indicated for adverse events or hypoglycemia.; Placebo provided QHS, BID, TID; Part 1 In the first two weeks of active treatment, subjects will receive double-blind therapy according to their randomized regimen (ORMD 0801 8 mg or 16 mg, or matched placebo) to be taken QHS or BID. Subjects will then enter Part 2 at the same dose and regimen administered in Part 1.
Part 2 Subjects will remain on fixed doses of ORMD-0801 (or matched placebo) for 10 weeks. Doses will not be adjusted unless clinically indicated for adverse events or hypoglycemia.
Intervention MeSH terms: Insulin; Insulin, Globin Zinc
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Single-Blind Placebo Run-in (Masking will be with Participant):
During the placebo run-in period, subjects will self-administer blinded placebo study medication at night prior to bedtime (@10 PM ± 90 min. each night, no sooner than 2 hrs. after dinner). Outpatient glycemic levels and adverse events will be measured using self-monitored blood glucose (SMBG) and recorded in a diary. Treatment Period (Masking: Participant, Care Provider, Investigator, Outcomes Assessor) There are 2 Cohorts, A and B.
Part 1 In the first 2 weeks of active treatment, subjects will receive double-blind therapy according to their randomized regimen (placebo or ORMD-0801) to be taken QHS (bedtime), BID (2 X / day) or TID.
Part 2 Subjects will remain on fixed doses of ORMD-0801 or matched placebo for 10 weeks. Doses will not be adjusted unless clinically indicated for adverse events or hypoglycemia. Treatment arms will consist of subjects receiving ORMD-0801 QHS, BID, and TID versus placebo.
Enrollment: 373.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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).
    

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.