Type 2 Diabetes Mellitus

Primary Efficacy Objective: The primary efficacy objective of this trial is to evaluate the placebo-adjusted change in hemoglobin A1c (HbA1c) from baseline after 24 weeks of exposure to bexagliflozin in type 2 diabetic subjects at high risk of cardiovascular adverse events. Secondary Efficacy Objectives: The key secondary efficacy objectives are: • To evaluate the effect of bexagliflozin on the change in body weight from baseline to week 48 in randomized subjects with a BMI ≥ 25 kg/m2 compared to placebo • To evaluate the effect of bexagliflozin on the change in systolic blood pressure (SBP) from baseline to week 24 in subjects with baseline systolic blood pressure ≥ 140 mmHg compared to placebo Additional exploratory efficacy objectives are: • To assess the effect of bexagliflozin treatment on the change in HbA1c versus placebo over time • To evaluate the effect of bexagliflozin treatment on the change in fasting plasma glucose (FPG) versus placebo over time • To measure the proportion of subjects requiring an intensification of anti-diabetic regimen versus placebo over time • To measure the proportion of subjects requiring a relaxation of their anti-diabetic regimen versus placebo over time • To measure the incidence of hospitalization for heart failure among all subjects and among subjects with a history of heart failure at baseline

Bexagliflozin Tablets

Bexagliflozin

tablet

20

Primary efficacy endpoint:
• Change in HbA1c from baseline to week 24, compared to placebo
Secondary efficacy endpoints:
• Change in body weight from baseline to week 48 in subjects with a BMI ≥ 25 kg/m2
• Change in SBP from baseline to week 24 in subjects with baseline systolic blood pressure
≥ 140 mmHg
Exploratory efficacy end points:
• Change in HbA1c from baseline over time
• Change in FPG from baseline over time
• Change in body weight from baseline over time
• Change in SBP over time
• Requirement of additional anti-diabetic medications, including insulin, over time
• Requirement of reduced anti-diabetic medications, including insulin, over time
• Incidence of hospitalization for heart failure among all subjects and among subjects who
have a history of heart failure

Inclusion Criteria
The study population will include:
1. Male or female adult subjects with an age ≥40 years
2. Subjects with a diagnosis of T2DM
3. Subjects with HbA1c values of 7.5 – 11%, inclusive
4. Subjects with fasting plasma glucose (FPG) ≤ 250 mg/dL at screening
5. Subjects who have a regimen for treatment of T2DM that has been stable for the past
3 months. A stable regimen is defined as: no changes in dose or frequency of OHAs or
GLP-1 agonists, or < 20% variability in total daily insulin dose.
6. Subjects who present with at least one of the following 3 histories:
Group 1: A history of atherosclerotic vascular disease as defined by one or more of the
following: a) myocardial infarction (MI) or ischemic (non-hemorrhagic) stroke >
3 months but ≤ 5 years prior to screening or b) documented history of coronary,
carotid, or peripheral arterial revascularization (coronary artery bypass grafting
must have occurred ≥ 5 years prior to screening)
Group 2: A history of NYHA class II or class III heart failure (Appendix 4) at the time of
screening with a left ventricular ejection fraction (LVEF) ≤ 40% and no
subsequent LVEF > 40% documented within 6 months of screening. No more
than 200 subjects with class II NYHA heart failure will be randomized in the
study.
Group 3: Age ≥ 55 years with 2 or more of the following: a) diabetes duration of ≥
10 years, b) uncontrolled hypertension defined as SBP > 140 mmHg despite 3 or
more anti-hypertensive medications c) current smoking, d) urine
albumin:creatinine ratio (UACR) > 30 mg/g, e) eGFR of 45 to 60 mL/min/
1.73 m
2
, or f) HDL < 1 mmol/L (38 mg/dL)
7. Female subjects of childbearing potential who are willing to use an adequate method of
contraception and to not become pregnant for the duration of the study. Adequate
contraceptive measures include, but are not limited to, oral contraceptives, intrauterine
devices, Depo-Provera, Norplant, hormonal contraceptive implants, bilateral tubal
ligation, partner with vasectomy, condom or diaphragm plus contraceptive sponge,
foam, or jelly, and abstinence
8. Subjects who are willing and able to return for all clinic visits and to complete all studyrequired procedures, including self-monitored blood glucose (SMBG) measurement
9. Subjects who receive anti-hypertensive medications at a stable dosage for ≥ 2 weeks
prior to randomization
10. Subjects who receive lipid modifying therapy on a stable regimen for 6 weeks prior to
randomization
11. Subjects who have SBP < 170 mmHg and DBP < 110 mmHg at screening.

Exclusion Criteria
Patients who exhibit any of the following characteristics will be excluded from the study.
1. Diagnosis of type 1 diabetes mellitus or maturity–onset/diabetes of the young (MODY)
2. Hemoglobinopathy that affects HbA1c measurement
3. Frequent symptomatic hypoglycemia (greater than one episode per week on average)
4. Genitourinary tract infection within 6 weeks of screening or history of ≥ 3 genitourinary
infections requiring treatment within the last 6 months
5. Cancer, active or in remission for < 3 years (Non-melanoma skin cancer or basal cell
carcinoma or carcinoma in situ of the cervix will not be grounds for exclusion)
6. History of alcohol or illicit drug abuse in the past 2 years
7. Evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase > 1.5 x
upper limit of normal (ULN) with the exception of isolated Gilbert’s syndrome); or
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x ULN
8. History of MI, stroke or hospitalization for heart failure in the prior 3 months
9. Evidence of NYHA class IV heart failure at screening or randomization
10. Presently scheduled for percutaneous coronary intervention, coronary artery bypass
grafting or a surgical procedure
11. Previous treatment with bexagliflozin or EGT0001474
12. Currently or within 3 months of taking any SGLT2 inhibitors (Appendix 3)
13. Any condition, disease, disorder, or clinically relevant laboratory abnormality that, in
the opinion of the PI, would jeopardize the subject’s appropriate participation in this
study or obscure the effects of treatment
14. Prior renal transplantation or evidence of nephrotic syndrome, defined as a urine
albumin: creatinine ratio (UACR) > 2000 mg/g, at screening
15. Implantation of a cardiac resynchronization therapy device within 3 months prior to
screening or intent to implant a cardiac resynchronization therapy (CRT) within 6
months following screening
16. Diagnosis of peripartum or chemotherapy-induced cardiomyopathy within 12 months
prior to screening
17. Symptomatic bradycardia or second or third degree atrioventricular block without a
pacemaker
18. eGFR, as calculated by the modification of diet in renal disease study equation
(MDRD), < 45 mL/min/1.73 m2
or requiring dialysis
19. Pregnant or nursing
20. Currently participating in another interventional trial.