Safety and Efficacy of Bexagliflozin Compared to Placebo as Add-on Therapy to Metformin in Type 2 Diabetes Subjects

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Bexagliflozin in Subjects With Type 2 Diabetes Mellitus Who Are Not Adequately Controlled by Metformin Alone

The purpose of this study is to investigate the effect of bexagliflozin compared to placebo as an add-on therapy to metformin in lowering hemoglobin A1c (HbA1c) levels in subjects with type 2 diabetes mellitus (T2DM).

Approximately 300 subjects with inadequately controlled T2DM on metformin were to be recruited from the United States and Japan. Subjects were randomly assigned to receive bexagliflozin tablets, 20 mg, or bexagliflozin tablets, placebo, in a ratio of 1:1 once daily for 24 weeks. Subjects were to continue taking metformin for the duration of the study. The study also enrolled 50 subjects with extremely poorly controlled T2DM on metformin to receive open-label bexagliflozin tablets, 20 mg, for 24 weeks.

The subjects were required to meet the following criteria at the time of enrollment to be eligible for the study:

1. Had been age ≥ 20 years at screening. Women of childbearing potential were required to have tested negative for pregnancy and have agreed to abstinence or contraception for the duration of the study to avoid any possible pregnancy. Females who were surgically sterile (hysterectomy, oophorectomy) or postmenopausal (absence of menses greater than 12 months) were eligible if they had tested negative for pregnancy at screening.
2. a) Had a history of T2DM with an HbA1c level of ≥ 7.5% and ≤ 10.5% at screening, or b) Had a history of T2DM with an HbA1c level of >10.5% and ≤ 12.0% at screening
3. Had been prescribed a stable dose of metformin (≥1500 mg per day in the US or ≥ 1000 mg per day in Japan) as their sole anti-diabetic medication
4. Had a body mass index (BMI) ≤ 45 kg m-2
5. Had been able to comprehend and willing to provide written informed consent in accordance with institutional and regulatory guidelines
6. Had no recent changes to their medications for hypertension or hyperlipidemia (if applicable)
7. Had the ability to regularly self-administer medication, as evidenced by consumption of all, or at worst one less than all, doses of run-in medication prior to randomization

Subjects who met any of the following criteria were to be excluded from the study:

1. Had a diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young
2. Were pregnant or breastfeeding
3. Had one or more hemoglobin alleles that affect HbA1c measurement
4. Had a history of genitourinary tract infection (e.g., UTI, GMI, vaginitis, balanitis) within 6 weeks of screening or a history of ≥ 3 genitourinary infections requiring treatment within 6 months of screening
5. Had an estimated glomerular filtration rate (eGFR), as calculated by the modification of diet in renal disease study equation (MDRD), < 60 mL min-1 per 1.73 m2
6. Had a sitting systolic blood pressure >180 mmHg or a sitting diastolic blood pressure > 110 mmHg at screening
7. Had exposure to hypoglycemic agent(s) other than metformin during the 8 weeks prior to screening
8. Had a history of illicit drug use or alcohol abuse in the past 2 years
9. Had a life expectancy < 2 years
10. Had a diagnosis of New York Heart Association (NYHA) Class IV heart failure within 3 months of screening
11. Had experienced an MI, unstable angina, stroke, or hospitalization for heart failure within 3 months of screening
12. Had exposure to an investigational drug within 30 days
13. Had a previous exposure to bexagliflozin or EGT0001474
14. Had a history of SGLT2 inhibitor treatment
15. Were participating in another interventional trial
16. Were not able to comply with the study scheduled visits
17. Had any condition, disease, disorder, or clinically relevant abnormality that, in the opinion of the primary investigator, would jeopardize the subject's appropriate participation in this study or obscure the effects of treatment
18. Had an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 × ULN or total bilirubin ≥ 1.5 × ULN at screening