A Phase 3 Study to Evaluate the Efficacy and Safety of ORMD-0801 in Subjects With Type 2 Diabetes Mellitus.

In this randomized, double-blind, double dummy, placebo-controlled study, approximately 300 eligible subjects with T2DM and inadequate control on at least one to three glucose-lowering agents will undergo an initial 4-week Screening Period. This will be followed by a 26-week Double-Blind Treatment Period, commencing with a safety Follow-up Visit four weeks after the completion of the trial. Analysis for the primary and secondary endpoints will be provided for the following subgroups of baseline factors:

• Sex (Male, Female)
• Age Group (60 years and younger, over 60 years)
• Baseline A1C (Less than or equal to 9.0, Greater than 9.0)
• Race
• Ethnicity

Screening Period

The Investigator will review the aim of the study, study procedures and potential risks and benefits. These subjects will then sign a written informed consent during the Screening Visit 1 (Screen 1) following which various study procedures will be performed (refer to Table 2). They will be scheduled to return to the clinic 10 days prior to randomization for Screening Visit 2 (Screen 2). At this visit, a CGM sensor will be placed with appropriate instructions by the study team for a 10-day blinded continuous glucose monitoring (CGM) data collection by the site. Subjects will then return to the clinic after 10 days (± 1-day) for removal of the CGM sensor. The subjects will be randomized to one of the four arms of the study treatment.

Treatment Period

After the Screening Period, subjects will be randomized to 26 weeks of Double-Blind Treatment.

In a double-blind, double dummy randomization scheme, subjects will be randomized to one of the following four treatment arms:

• ORMD-0801 8 mg once-daily at night - QD: 1 x 8 mg capsule between 8 PM to 12 Midnight and no sooner than 1 hour after dinner and 2 placebo capsules (1 in the morning and 1 at night).
• ORMD-0801 8 mg twice daily - BID: 1 x 8 mg capsule each morning approximately 45 minutes (±15 minutes) prior to breakfast and 1 x 8 mg capsule each night prior to bedtime (between 8 PM to 12 Midnight and no sooner than 1 hour after dinner) and 1 placebo capsule at night.
• ORMD-0801 16 mg once-daily at night - QD: 2 x 8 mg capsules between 8 PM to 12 Midnight and no sooner than 1 hour after dinner and 1 placebo capsule in the morning.
• Placebo. During the Double-Blind Treatment Period commencing at Week 0 (Visit 1, CGM removal), subjects will return to the clinic at Week 24 - Visit 5 (10 days prior to Week 26 for CGM application) and Week 26 - Visit 6 (CGM removal and end of Double-Blind Treatment Period visit).

The visit requiring CGM application will occur 10 days prior to the CGM removal visit within ± 1-day window.

Safety Follow-up/End of Study All subjects completing the trial will return to the clinic in 4 weeks ± 3 days for a safety Follow-up Visit. Study procedures and assessments will be performed.

Subjects withdrawing prematurely from the trial will have the early termination (ET) visit procedures completed. All patients will continue to be followed in accordance with ITT principles to avoid lost to follow-up and missing data.

Throughout the course of the study, subjects will measure and record fasting blood glucose levels at least 2-3 times a week [self-monitored blood glucose (SMBG)] or when they experience any symptoms of hypoglycemia using a glucose meter. Subjects will be provided a paper diary at each clinic visit and trained to record information related to fasting blood glucose and description of hypoglycemic events: time and date of occurrence; symptoms experienced, if any; treatment given, if any; and specific circumstances. Subjects will be required to bring the paper diary at each clinic visit where data will be reviewed.

Inclusion criteria

• Male and female subjects aged ≥ 50 years.
• Established diagnosis of T2DM for at least 6 months prior to Screening AND an A1C ≥ 7.2% but ≤ 10.0% at Screening.
• On a stable dose of at least one and up to three of the following glucose-lowering agents: Metformin, sulfonylurea, DPP-4 inhibitor, SGLT-2 inhibitor, thiazolidinedione, insulin secretagogue, oral or injected GLP-1 receptor agonists, glucosidase inhibitor, or pramlintide (injected insulin is excluded) for a minimum of 3 months prior to Screening.
• Body mass index (BMI) of ≤ 28 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 ≥ 30 ml/min.
• Females of childbearing potential must:
• - a. Have a negative serum pregnancy test result at Screening.
• - b. Agree to avoid becoming pregnant while receiving IP for at least 30 days prior to IP administration, during the entire study, and for 30 days following their last dose of IP.
• - c. Agree to use an acceptable method of contraception at least 30 days prior to IP administration, during the entire study, and for 30 days following their last dose of IP. Acceptable methods of contraception are hormonal contraception (contraceptive pill or injection) PLUS an additional barrier method of contraception such as a diaphragm, condom, sponge, or spermicide.
• - d. In the absence of hormonal contraception, double-barrier methods must be used which include a combination of any two of the following: diaphragm, condom, copper intrauterine device, sponge, or spermicide, and must be used for at least 30 days prior to administration of IP, during the entire study, and for 30 days following their last dose of IP.
• - e. Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject's preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.
• - f. Females who are not of childbearing potential are defined as:
• - - - - - i. Postmenopausal (defined as at least 12 months with no menses in women ≥ 45 years of age); OR
• - - - - - ii. Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; OR
• - - - - - iii. Have a congenital or acquired condition that prevents childbearing.

Exclusion criteria

• Type 1 diabetes by history.
• Diabetes attributable to other secondary causes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ transplant).
• Treatment involving injected insulin within 3 months prior to Visit 1.
• A history of > 2 episodes of severe hypoglycemia within 6 months prior to Screening.
• A history of hypoglycemic unawareness.
• A history of unstable angina or myocardial infarction within 6 months prior to Screening, New York Heart Association (NYHA) Grade 3 or 4 congestive heart failure (CHF), valvular heart disease, ventricular cardiac arrhythmia requiring treatment, pulmonary hypertension, cardiac surgery, coronary angioplasty, stroke, or transient ischemic attack (TIA) within 6 months prior to Screening.
• A history of uncontrolled or untreated severe hypertension defined as systolic blood pressure above or equal to 160 mmHg and/or diastolic blood pressure above or equal to 100 mmHg. A single repeat measurement will be permitted
• Renal dysfunction: eGFR < 30 mL/min.
• A history of or active proliferative retinopathy requiring treatment.
• Psychiatric disorders that, per Investigator judgment, may have impact on the safety of the subject or interfere with subject's participation or compliance in the study.
• Laboratory abnormalities at Screening including:
• - - a. Abnormal serum thyrotropin (TSH) levels below the lower limit of normal or >1.5X the upper limit of normal; a single repeat test is allowable.
• - - b. Elevated liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP)) > 3X the upper limit of normal; a single repeat test is allowable.
• - - c. Very elevated fasting triglyceride levels (> 600 mg/dL); a single repeat test is allowable.
• - - d. Any relevant abnormality that would interfere with the efficacy or the safety assessments during study treatment administration.
• Positive history of active liver disease (other than non-alcoholic hepatic steatosis), primary biliary cirrhosis, or active symptomatic gallbladder disease.
• Positive results for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus ribonucleic acid (RNA).
• Patient has active or history of neoplastic disease (except for adequately treated non-invasive basal cell and/or squamous cell carcinoma or carcinoma in situ of the cervix) within the past 5 years prior to baseline.
• Use of the following medications:
• - - -a. History of use of any injectable insulin (greater than 7 days) within 6 months prior to Screening.
• - - -b. Administration of thyroid preparations or thyroxine (except in subjects on stable replacement therapy) within 6 weeks prior to Screening.
• - - - c. Use of oral, intravenous, or intramuscular steroids for one month prior to enrollment. Intra-articular and/or topical corticosteroids are not considered systemic.
• - - - d. Concurrent use of medications known to modify glucose metabolism or to decrease the ability to recover from hypoglycemia such as oral, parenteral, and immunosuppressive or immunomodulating agents. Inhaled nasal steroids are permissible.
• Known allergy to soy.
• Involvement in a weight loss program and is not in the maintenance phase, or subject has started weight loss medication (e.g., orlistat or liraglutide) within 3 months prior to Screening.
• Prior bariatric surgery.
• Subject is pregnant or breast-feeding.
• 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.
• Weight loss preparations either approved and marketed or used in OTC preparations except for GLP-1 used in the treatment of underlying diabetes.
• Any condition or other factor (at the Investigator's discretion) that is deemed unsuitable for subject enrollment into the study.