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

Phase 3

Completed

Interventions: Drug: Placebo for Bexagliflozin
Drug: Bexagliflozin
Drug: Placebo for Glimepiride
Drug: Glimepiride

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

Detailed Description: Approximately 420 subjects with inadequately controlled T2DM on metformin will be recruited from North America and Europe. Subjects will be randomly assigned to receive bexagliflozin tablets, 20 mg, or glimepiride capsules, 2, 4 or 6 mg, in a ratio of 1:1 once daily for 96 weeks. Subjects will continue to take metformin for the duration of the study.

Recruitment & Eligibility

Inclusion Criteria

Diagnosis of T2DM
Currently taking metformin or taking metformin and one additional oral medication for diabetes
Body Mass Index (BMI) ≤ 45 kg/m2
Stable dose of blood pressure or cholesterol medications (if applicable) for at least 30 days

Exclusion Criteria

Hypersensitivity or other contraindication to the safe use of sulfonylurea or glimepiride
Diagnosis of type 1 diabetes mellitus or maturity-onset/diabetes of the young
Current use of injected therapy for treatment of diabetes (insulin or GLP-1 receptor agonist therapy) or thiazolidinedione class drugs
History of genitourinary tract infections
Evidence of abnormal liver function
Myocardial infarction, stroke or hospitalization for heart failure within 3 months of screening
Prior kidney transplant or evidence of kidney problems
Pregnant or nursing

Arm && Interventions

Group	Intervention	Description
Bexagliflozin	Placebo for Glimepiride	Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride daily for the duration of the study.
Glimepiride	Placebo for Bexagliflozin	Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study.
Glimepiride	Glimepiride	Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study.
Bexagliflozin	Bexagliflozin	Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride daily for the duration of the study.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in HbA1c at Week 60	Baseline and Week 60	The primary objective is to demonstrate that bexagliflozin is non-inferior to glimepiride by evaluating the treatment effect on HbA1c reduction at week 60 in subjects whose T2DM is inadequately controlled by metformin. The least square mean (LSM) change from baseline to Week 60 was analyzed using a mixed model repeated measures (MMRM) analysis of covariance model (ANCOVA).

Secondary Outcome Measures

Name	Time	Method
Difference in Proportion of Subjects With ≥ 1 Severe or Documented Symptomatic Hypoglycemia Events Over 96 Weeks	During the 96 week treatment period	The difference in proportion of subjects with ≥ 1 severe or documented symptomatic hypoglycemia events in the bexagliflozin group compared with glimepiride group over 96 weeks is analyzed using a logistic regression model. The full model included region, baseline HbA1c value, background treatment status (metformin or metformin + OHA), eGFR at baseline ≥ 90 or \< 90 mL min 1 per 1.73 m2), treatment as a fixed effect covariate.
Change From Baseline in Body Weight at Week 60 for Subjects With Baseline BMI ≥ 25 kg/m2	Baseline and 60 weeks	Least squares (LS) mean treatment difference between the bexagliflozin group and placebo group in the change of body weight in subjects with baseline BMI ≥ 25 kg/m2 at week 60 is analyzed using ANCOVA.
Change From Baseline in Systolic Blood Pressure (SBP) at Week 60 for Subjects With Baseline SBP ≥ 140 mmHg	Baseline and 60 weeks	Least squares (LS) mean treatment difference between the bexagliflozin group and placebo group in the change of SBP in subjects with baseline SBP ≥ 140 mmHg at week 60 is analyzed using ANCOVA.
Superiority of Bexagliflozin Over Glimepiride in HbA1c Reduction at Week 60.	Baseline to Week 60	Superiority of bexagliflozin over glimepiride in HbA1c reduction from baseline to week 60 will be declared if the upper bound of 95% CI is less than 0.