A Dose Range Finding Study to Evaluate the Effect of Bexagliflozin Tablets in Subjects With Type 2 Diabetes Mellitus

The study was a phase 2b multicenter, double-blind, placebo-controlled parallel group study to assess the effect of once daily bexagliflozin tablets on HbA1c in either treatment-naïve T2DM subjects or in subjects who were treated with one oral anti-diabetic agent. Treatment naïve subjects were eligible if their HbA1c values were between 7% and 8.5% at the screening visit while subjects who were treated with one oral hypoglycemic agent (OHA) were eligible if their HbA1c value was between 6.5% and 8.5% at screening and underwent a 6 or 10 week washout period. In addition, all eligible subjects underwent a two week placebo run-in period and those who showed good compliance in taking study medication (i.e., missed no more than one dose during the run-in period) during this period and whose HbA1c values were between 7 and 8.5% at the end of the run-in period were eligible for randomization.

The following subjects were eligible for randomization:

• men or women ≥ 20 years of age at screening. Women of childbearing potential must test negative by urine pregnancy test.
• were treatment naïve or taking one oral anti-diabetic medication in combination with diet and exercise
• were diagnosed with T2DM with HbA1c levels at screening between 7.0% and 8.5% (inclusive) if treatment naïve or with HbA1c levels between 6.5 and 8.5% (inclusive) if on one oral anti-diabetic medication
• had a body mass index (BMI) ≤ 40 kg/m2
• were taking stable doses of medication for hypertension or hyperlipidemia that has not changed for at least 30 days prior to screening (if applicable)
• were able to comprehend the study participation requirements and willing to provide written informed consent in accordance with institutional and regulatory guidelines
• were able to maintain adequate glycemic control at the run-in visit (for subjects who complete the washout)
• had an HbA1c between 7.0 and 8.5% (inclusive) prior to randomization (day -3 to -5)
• were capable of adhering to the investigational product administration requirements as evidenced by omission of no more than one dose of run-in medication

Subjects who exhibited any of the following characteristics were to be ineligible for randomization:

• Diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young
• Used parenteral therapy for treatment of diabetes
• Pregnancy or current breastfeeding status
• Hemoglobinopathy or carrier status for hemoglobin alleles that affect HbA1c measurement
• Genitourinary tract infection within 6 weeks of screening or history of ≥3 genitourinary infections requiring treatment within 6 months of screening
• Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 at screening.
• Uncontrolled hypertension at screening
• A positive result on hepatitis B surface antigen, hepatitis C, or positive result from screen for drugs of abuse
• History of human immunodeficiency virus infection
• Life expectancy < 2 years
• History of New York Heart Association Class 4 heart failure within 3 months of screening
• History of myocardial infarction, unstable angina, stroke, or hospitalization for heart failure within 3 months of screening
• History of treatment with an investigational drug within 30 days or within 7 half lives of the investigational drug, whichever is longer
• Previous treatment with bexagliflozin
• Had taken or within 6 months of taking any Sodium Glucose Transporter 2 (SGLT2) inhibitors prior to screening
• Participation of another interventional trial
• Not able to comply with the study scheduled visits
• Affected by any condition, disease, disorder, or clinically relevant abnormality that, in the opinion of the investigator, would jeopardize the subject's appropriate participation in this study.
• Liver function tests resulting in Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 2.5 x upper limit of normal (ULN) or total bilirubin ≥ 1.5 x ULN, with the exception of isolated Gilbert's syndrome ,at screening
• Exhibited fasting plasma glucose ≥ 250 mg/dL (13.9 mmol/L) on two or more consecutive days prior to randomization or exhibited severe clinical signs or symptoms of hyperglycemia during the washout or run-in periods, including weight loss, blurred vision, increased thirst, or increased urination, or fatigue
• Fasting Plasma Glucose ≥ 250 mg/dL at randomization
• Prior renal transplantation or evidence of nephrotic syndrome, defined as a urine albumin-to-creatinine ratio (UACR) > 2000 mg/g at screening