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

Study Overview
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Brief Summary
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The purpose of this study was to investigate the effect of bexagliflozin in lowering hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM). Bexagliflozin is an orally administered drug for the treatment of T2DM and is classified as a Sodium Glucose co-Transporter 2 (SGLT2) Inhibitor. This study was to enroll both treatment naive and those subjects previously treated with one oral hypoglycemic agent (OHA). Approximately 320 subjects eligible for randomization was to receive bexagliflozin tablets, 5, 10, 20 mg or placebo, once daily for 12 weeks in an outpatient setting.

Detailed Description
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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.

Official Title
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A Phase 2b, Multi-center, Double-blind, Placebo-controlled, Dose Range Finding Study to Evaluate the Effect of Bexagliflozin Tablets on HbA1c in Subjects With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Bexagliflozin tablets
* Drug: Bexagliflozin tablets, placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 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 tablets, 5 mg<br>Bexagliflozin tablets, 5 mg, once daily by mouth before breakfast | Drug: Bexagliflozin tablets<br>* Bexagliflozin tablets are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans.<br>* Other names: Code name: EGT0001442;|
| Active Comparator: Bexagliflozin tablets, 10 mg<br>Bexagliflozin tablets, 10 mg, once daily by mouth before breakfast | Drug: Bexagliflozin tablets<br>* Bexagliflozin tablets are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans.<br>* Other names: Code name: EGT0001442;|
| Active Comparator: Bexagliflozin tablets, 20 mg<br>Bexagliflozin tablets, 20 mg, once daily by mouth before breakfast | Drug: Bexagliflozin tablets<br>* Bexagliflozin tablets are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans.<br>* Other names: Code name: EGT0001442;|
| Placebo Comparator: Bexagliflozin tablets, placebo<br>Bexagliflozin tablets, placebo, once daily by mouth before breakfast | Drug: Bexagliflozin tablets, placebo<br>* Bexagliflozin tablets, placebo, are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c After 12 Weeks of Treatment | Mixed model repeated measures (MMRM) analysis of covariance model (ANCOVA) with baseline HbA1c as a covariate will be fit to the available data, incorporating all visits at which HbA1c was measured for each subject including scheduled visits at Weeks 2, 6, and 12 as well as unscheduled visits for measurements of HbA1c. Treatment (placebo, 5 mg, 10 mg, 20 mg), study center, prior anti-diabetic treatment status, study visit and treatment-by-visit interaction will be applied as fixed effects and subject as a random effect. The least square mean (LSM) change from baseline to Week 12 was analyzed using the Mixed-Effect Model Repeated Measure (MMRM) Analysis of Covariance (ANCOVA) model using 95% Confidence Intervals (CIs) for the between-group mean changes. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects With HbA1c < 7% | To assess the efficacy of bexagliflozin based on the proportion of subjects who reach the American Diabetes Associate (ADA) and the Japan Diabetes Society target HbA1c of <7%. | Baseline to up to 12 weeks | 
| Change in Body Weight Over Time | The body weight was analyzed on the full analysis set using the MMRM ANCOVA model used for the primary efficacy analysis. | Baseline to Week 2, Week 6 and Week 12 | 
| Change in Fasting Plasma Glucose (FPG) Over Time | The fasting plasma glucose (FPG) was analyzed on the full analysis set using the same MMRM ANCOVA model used in the primary efficacy analysis. | Baseline to Week 2, Week 6 and Week 12 | 
| Change in Systolic and Diastolic Blood Pressure Over Time | The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were analyzed on the full analysis set using the same MMRM ANCOVA model used in the primary efficacy analysis. | Baseline to Week 2, Week 6 and Week 12 | 
| Change in HbA1c Over Time | The least square mean (LSM) change from baseline to Week 2, Week 6 and Week 12 was analyzed using the Mixed-Effect Model Repeated Measure (MMRM) Analysis of Covariance (ANCOVA) model using 95% Confidence Intervals (CIs) for the between-group mean changes. The LSM change was calculated by excluding HbA1c data obtained after rescue medication. | Baseline to Week 2, Week 6 and Week 12 |