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

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

Detailed Description
-----------------
This was a phase 3, multi-center, randomized, double-blind, parallel-group study to demonstrate that bexagliflozin was non-inferior to sitagliptin as add-on therapy in subjects whose T2DM was not adequately controlled by metformin treatment alone. The primary effectiveness endpoint was the change in HbA1c from baseline at week 24. At the time of screening, all subjects were to have taken metformin at a stable dose of ≥ 1500 mg per day for ≥ 8 weeks and have received diet and exercise counseling. A total of 374 eligible subjects were to be enrolled in the study. Subjects who successfully completed a 1-week run-in and who met all eligibility criteria were to be randomized in a 1:1 ratio to receive once daily double-blind treatment of either active bexagliflozin tablets with placebo sitagliptin tablets or placebo bexagliflozin tablets and active sitagliptin tablets. The study subjects were to continue receiving open-labeled metformin during the entire study at a stable dose and frequency. The treatment period was 24 weeks and was conducted in an outpatient setting. Randomization was stratified by HbA1c (≤ 8.5% vs. ˃ 8.5%) values. Symptoms and blood sugars related to the occurrence of hyperglycemia, hypoglycemic events or symptoms that could indicate ketoacidosis were to be recorded. Bexagliflozin tablets, 20 mg or placebo, and sitagliptin tablets, 100 mg or placebo, were to be taken once daily at approximately the same time each day either before or after breakfast. Background metformin was to be taken at the same dose and frequency from screening throughout the entire study. Each subject was advised to return to the clinic at weeks 6, 12, 18 and 24 for efficacy assessment and safety monitoring, including review of AEs and concomitant medication, vital signs, ECG, physical examination and blood and urine specimen collections. Subjects were to return to the clinic for a follow-up exit visit at week 26 or 2 weeks after the last dose of study drugs if subjects withdrew from the study prior to week 24.

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

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Bexagliflozin
* Drug: Sitagliptin
* Drug: Placebo for sitagliptin
* Drug: Placebo for bexagliflozin


Participation Criteria
=================
Eligibility Criteria
-----------------
Each subject was required to meet the following criteria at the time of enrollment to be eligible for the study: To have been male or female adults ≥ 18 years of age. To have been negative on the urine pregnancy test and agreed to abstain from coitus or use contraception during the entire study if a subject was female of childbearing potential. To have had a diagnosis of T2DM with HbA1c levels between 7.0% and 11% (inclusive) at the time of screening. To have been treated with a stable dose of ≥ 1500 mg/day metformin only along with diet and exercise counseling for at least 8 weeks at the time of screening. To have had a BMI ≤ 45 kg per m2 at the time of screening. To have been taking stable doses of treatment for dyslipidemia and/or hypertension for 30 days if applicable. To have been willing and able to return for all clinic visits and to complete all study-required procedures. To have adhered to the investigational product administration requirements as evidenced by missing no more than 1 day of run-in medications. Potential subjects who exhibited any of the following characteristics were to be excluded from the study: Diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young (MODY) Hemoglobinopathy that affected HbA1c measurement Any contraindication to the safe use of DPP-4 therapy or sitagliptin, including known hypersensitivity reaction History of pancreatitis Genitourinary tract infection within 6 weeks of screening or history of ≥ 3 genitourinary infections requiring treatment within 6 months from the time of screening Cancer, active or in remission, for < 3 years History of alcohol or illicit drug abuse in the past 2 years Triglycerides > 500 mg dL-1 at Visit V1 Evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase > 1.5 x upper limit of normal (ULN) with the exception of isolated Gilbert's syndrome); or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x ULN Estimated GFR, as calculated by the modification of diet in renal disease study equation (MDRD), < 60 mL min-1 per 1.73 m2 at the time of screening. Uncontrolled hypertension (SBP > 160 mm Hg or diastolic BP > 95 mm Hg) at Visit V1 Life expectancy < 2 years History of MI, unstable angina, stroke or hospitalization for heart failure within 3 months at the time 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 or EGT0001474 study drug Currently or within 3 months of taking any SGLT2 inhibitor Currently participating in another interventional trial Prior renal transplantation or evidence of nephrotic syndrome (defined as a urine albumin-to-creatinine ratio (UACR) > 1500 mg g-1 at the time of screening). Any condition, disease, disorder or clinically relevant abnormality that could have jeopardized the subject's appropriate participation in this study or obscure the effects of treatment Female subjects who were pregnant or nursing Two or more consecutive SMBG measures ≥ 250 mg dL-1 (13.9 mmol L-1) prior to randomization accompanied by clinical signs or symptoms of hyperglycemia prior to randomization, including weight loss, blurred vision, increased thirst increased urination, or fatigue

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 sitagliptin daily for the duration of the study. | Drug: Bexagliflozin<br>* tablets containing 20 mg bexagliflozin<br>* Other names: EGT0001442, EGT0001474;Drug: Placebo for sitagliptin<br>* inactive tablets to match the appearance of sitagliptin tablets<br>|
| Active Comparator: Sitagliptin<br>Subjects will receive a sitagliptin tablet, 100 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: Sitagliptin<br>* tablets containing 100 mg sitagliptin<br>* Other names: Januvia;Drug: Placebo for bexagliflozin<br>* inactive tablets to match the appearance of bexagliflozin tablets<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c From Baseline to Week 24 | The primary efficacy objective is to demonstrate that bexagliflozin is non-inferior to sitagliptin by evaluating the treatment effect on hemoglobin A1c (HbA1c) reduction at week 24 in subjects whose type 2 diabetes mellitus (T2DM) is inadequately controlled by metformin. | Baseline to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FPG From Baseline at Week 24 | To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in fasting plasma glucose (FPG) at week 24 | Baseline to week 24 | 
| Change in Body Weight in Subjects With Baseline BMI ≥ 25 kg/m2 at Week 24 | To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in body weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 at week 24 | Baseline to week 24 | 
| Change in SBP in Subjects From Baseline at Week 24 | To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in systolic blood pressure (SBP) in subjects at week 24 | Baseline to week 24 |