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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 3, Randomized, Double-blind, Active-controlled Study to Evaluate the Effects of Bexagliflozin Versus Glimepiride in Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control by Metformin

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Bexagliflozin
* Drug: Placebo for Bexagliflozin
* Drug: Glimepiride
* Drug: Placebo for Glimepiride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bexagliflozin<br>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. | Drug: Bexagliflozin<br>* 20 mg, tablet<br>* Other names: EGT0001442;Drug: Placebo for Glimepiride<br>* inactive capsules to match active comparator glimepiride<br>|
| Active Comparator: Glimepiride<br>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. | Drug: Placebo for Bexagliflozin<br>* inactive tablet to match active comparator bexagliflozin<br>Drug: Glimepiride<br>* 2, 4 or 6 mg, capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c at 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). | Baseline and Week 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Body Weight at Week 60 for Subjects With Baseline BMI ≥ 25 kg/m2 | 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. | Baseline and 60 weeks | 
| Change From Baseline in Systolic Blood Pressure (SBP) at Week 60 for Subjects With Baseline SBP ≥ 140 mmHg | 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. | Baseline and 60 weeks | 
| Difference in Proportion of Subjects With ≥ 1 Severe or Documented Symptomatic Hypoglycemia Events Over 96 Weeks | 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. | During the 96 week treatment period | 
| Superiority of Bexagliflozin Over Glimepiride in HbA1c Reduction at 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. | Baseline to Week 60 |