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

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Bexagliflozin in Subjects With Type 2 Diabetes Mellitus Who Are Not Adequately Controlled by Metformin Alone

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

Study Overview

• Status: Completed
• Conditions: Type2 Diabetes Mellitus
• Intervention / Treatment: Drug: Bexagliflozin tablets, 20 mg; Drug: Bexagliflozin tablets, placebo

Detailed Description

Approximately 300 subjects with inadequately controlled T2DM on metformin were to be recruited from the United States and Japan. Subjects were randomly assigned to receive bexagliflozin tablets, 20 mg, or bexagliflozin tablets, placebo, in a ratio of 1:1 once daily for 24 weeks. Subjects were to continue taking metformin for the duration of the study. The study also enrolled 50 subjects with extremely poorly controlled T2DM on metformin to receive open-label bexagliflozin tablets, 20 mg, for 24 weeks.

• Study Type: Interventional
• Enrollment (Actual): 351
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Fukuoka, Japan, 819-0006
    • Clinical Research Site 6040
  • Kyoto, Japan, 600-8898
    • Clinical Research Site 6043
  • Osaka, Japan, 536-0008
    • Clinical Research Site 6015
  • Tokyo, Japan, 108-0075
    • Clinical Research Site 6045
  • Tokyo, Japan, 166-0003
    • Clinical Research Site 6047
  • Aichi
    • Nagoya, Aichi, Japan, 456-0058
      • Clinical Research Site 6048
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 003-0023
      • Clinical Research Site 6050
  • Ibaraki
    • Koga, Ibaraki, Japan, 306-0232
      • Clinical Research Site 6041
  • Kanagawa
    • Atsugi, Kanagawa, Japan, 243-0035
      • Clinical Research Site 6029
    • Kamakura, Kanagawa, Japan, 547-0055
      • Clinical Research Site 6051
    • Yokohama, Kanagawa, Japan, 221-080
      • Clinical Research Site 6020
  • Meguro
    • Tokyo, Meguro, Japan, 153-0053
      • Clinical Research Site 6055
  • Osaka
    • Higashiosaka, Osaka, Japan, 577-0803
      • Clinical Research Site 6046
    • Kashiwara, Osaka, Japan, 582-0005
      • Clinical Research Site 6033
    • Toyonaka, Osaka, Japan, 560-0082
      • Clinical Research Site 6013
  • Saitama
    • Kawaguchi, Saitama, Japan, 332-0012
      • Clinical Research Site 6052
  • Tochigi
    • Shimotsuke, Tochigi, Japan, 329-0433
      • Clinical Research Site 6053
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • Clinical Research Site 1232
    • Birmingham, Alabama, United States, 35242
      • Clinical Research Site 1378
    • Foley, Alabama, United States, 36535
      • Clinical Research Site 1269
  • Arkansas
    • Little Rock, Arkansas, United States, 72209
      • Clinical Research Site 1363
  • California
    • Anaheim, California, United States, 92805
      • Clinical Research Site 1381
    • North Hollywood, California, United States, 91606
      • Clinical Research Site 1375
    • Norwalk, California, United States, 90650
      • Clinical Research Site 1365
  • Connecticut
    • Norwalk, Connecticut, United States, 06851
      • Clinical Research Site 1382
  • Florida
    • Hollywood, Florida, United States, 33024
      • Clinical Research Site 1372
    • Palm Springs, Florida, United States, 33461
      • Clinical Research Site 1362
    • Pembroke Pines, Florida, United States, 33026
      • Clinical Research Site 1373
  • Idaho
    • Nampa, Idaho, United States, 83686
      • Clinical Research Site 1376
  • Illinois
    • Chicago, Illinois, United States, 60602
      • Clinical Research Site 1366
  • Louisiana
    • New Orleans, Louisiana, United States, 70124
      • Clinical Research Site 1294
  • Missouri
    • Saint Louis, Missouri, United States, 63117
      • Clinical Research Site 1374
  • Nevada
    • Las Vegas, Nevada, United States, 89104
      • Clinical Research Site 1370
  • New Jersey
    • Berlin, New Jersey, United States, 08009
      • Clinical Research Site 1009
    • Trenton, New Jersey, United States, 08611
      • Clinical Research Site 1037
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Clinical Research Site 1286
  • New York
    • Bronx, New York, United States, 10455
      • Clinical Research Site 1275
    • New York, New York, United States, 10036
      • Clinical Research Site 1368
  • Oregon
    • Portland, Oregon, United States, 97239
      • Clinical Research Site 1019
  • Texas
    • Gonzales, Texas, United States, 78629
      • Clinical Research Site 1379
    • Houston, Texas, United States, 77051
      • Clinical Research Site 1369
    • San Antonio, Texas, United States, 78209
      • Clinical Research Site 1371
    • San Antonio, Texas, United States, 78258
      • Clinical Research Site 1360

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

The subjects were required to meet the following criteria at the time of enrollment to be eligible for the study:

1. Had been age ≥ 20 years at screening. Women of childbearing potential were required to have tested negative for pregnancy and have agreed to abstinence or contraception for the duration of the study to avoid any possible pregnancy. Females who were surgically sterile (hysterectomy, oophorectomy) or postmenopausal (absence of menses greater than 12 months) were eligible if they had tested negative for pregnancy at screening.
2. a) Had a history of T2DM with an HbA1c level of ≥ 7.5% and ≤ 10.5% at screening, or b) Had a history of T2DM with an HbA1c level of >10.5% and ≤ 12.0% at screening
3. Had been prescribed a stable dose of metformin (≥1500 mg per day in the US or ≥ 1000 mg per day in Japan) as their sole anti-diabetic medication
4. Had a body mass index (BMI) ≤ 45 kg m-2
5. Had been able to comprehend and willing to provide written informed consent in accordance with institutional and regulatory guidelines
6. Had no recent changes to their medications for hypertension or hyperlipidemia (if applicable)
7. Had the ability to regularly self-administer medication, as evidenced by consumption of all, or at worst one less than all, doses of run-in medication prior to randomization

Subjects who met any of the following criteria were to be excluded from the study:

1. Had a diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young
2. Were pregnant or breastfeeding
3. Had one or more hemoglobin alleles that affect HbA1c measurement
4. Had a history of genitourinary tract infection (e.g., UTI, GMI, vaginitis, balanitis) within 6 weeks of screening or a history of ≥ 3 genitourinary infections requiring treatment within 6 months of screening
5. Had an estimated glomerular filtration rate (eGFR), as calculated by the modification of diet in renal disease study equation (MDRD), < 60 mL min-1 per 1.73 m2
6. Had a sitting systolic blood pressure >180 mmHg or a sitting diastolic blood pressure > 110 mmHg at screening
7. Had exposure to hypoglycemic agent(s) other than metformin during the 8 weeks prior to screening
8. Had a history of illicit drug use or alcohol abuse in the past 2 years
9. Had a life expectancy < 2 years
10. Had a diagnosis of New York Heart Association (NYHA) Class IV heart failure within 3 months of screening
11. Had experienced an MI, unstable angina, stroke, or hospitalization for heart failure within 3 months of screening
12. Had exposure to an investigational drug within 30 days
13. Had a previous exposure to bexagliflozin or EGT0001474
14. Had a history of SGLT2 inhibitor treatment
15. Were participating in another interventional trial
16. Were not able to comply with the study scheduled visits
17. Had any condition, disease, disorder, or clinically relevant abnormality that, in the opinion of the primary investigator, would jeopardize the subject's appropriate participation in this study or obscure the effects of treatment
18. Had an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 × ULN or total bilirubin ≥ 1.5 × ULN at screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Bexagliflozin tablets, 20 mg; Double-Blind	Drug: Bexagliflozin tablets, 20 mg; Each subject will receive bexagliflozin, 20 mg once daily for the duration of the study.; Other Names: EGT0001442, EGT0001474
PLACEBO_COMPARATOR: Bexagliflozin tablets, Placebo; Double Blind	Drug: Bexagliflozin tablets, placebo; Each subject will receive placebo (inactive tablet) once daily for the duration of the study.
EXPERIMENTAL: Bexagliflozin Tablets, 20 mg; High Glycemic Group	Drug: Bexagliflozin tablets, 20 mg; Each subject will receive bexagliflozin, 20 mg once daily for the duration of the study.; Other Names: EGT0001442, EGT0001474

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HbA1c at Week 24 for Double-blind Group	HbA1c was obtained at baseline and at Week 24. The model-adjusted change from baseline was calculated using mixed-effects repeated measures analysis.	Baseline to week 24
Change From Baseline in HbA1c at Week 24 for High Glycemic Group	The change in HbA1c from baseline at Week 24 in High Glycemic Group was calculated by subtracting the mean HbA1c at baseline from the mean HbA1c at Week 24	Baseline to week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 for Double-blind Group	FPG was obtained at baseline and at Week 24. The model-adjusted change from baseline was calculated using mixed-effects repeated measures analysis.	Baseline, up to 24 weeks
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 for High Glycemic Group	The change in FPG from baseline at Week 24 for High Glycemic Group was calculated by subtracting the mean FPG at baseline from the mean FPG at Week 24	Baseline, up to 24 weeks
Change From Baseline in Systolic Blood Pressure (SBP) at Week 24	Changes from baseline at Week 24 in SBP for the double-blind group and high glycemic group	Baseline to week 24
Proportion of Subjects Achieving HbA1c < 7% Over Time for Double-blind Group	The proportion of subjects who achieved HbA1c < 7% at 6, 12, 18 and 24 weeks were calculated based on the number of subjects with a value at each time point for each group. The model-adjusted proportion was calculated based on a logistic analysis using Generalized Estimating Equation (GEE) logistic regression that includes country, treatment, visit, treatment-by-visit interaction and the baseline HbA1c value as a fixed effect covariate. An unstructured correlation structure will be used, or autoregressive if the model with the unstructured structure does not converge.	Baseline, up to 24 weeks
Proportion of Subjects Achieving HbA1c < 7% Over Time for High Glycemic Group	The proportion of subjects who achieved HbA1c < 7% at 6, 12, 18 and 24 weeks were calculated based on the number of subjects with a value at each time point for each group.	Baseline, up to 24 weeks
Change in Body Mass From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2 for Double-blind Group	Changes in body mass from baseline to week 24 was calculated based on LS means for both bexagliflozin and placebo groups.	Baseline to week 24
Change in Body Mass From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2 for High Glycemic Group	The change in body mass from baseline at week 24 for High Glycemic group was calculated by subtracting the mean body mass at baseline from the mean body mass at week 24	Baseline to week 24
Change From Baseline in HbA1c Over Time in Double-blind Treatment Group	The change from baseline in HbA1c at 6, 12, 18 and 24 weeks was calculated based on the number of subjects with a value at each time point for each group. The model-adjusted change from baseline was calculated based on a mixed-effects repeated measures analysis that includes country, treatment, visit, treatment-by-visit interaction and the baseline HbA1c value as a fixed effect covariate.	Baseline, up to 24 weeks
Change in HbA1c Over Time Among Subjects Who Have Baseline HbA1c of > 10.5% and ≤ 12.0%	The change from baseline in HbA1c at 6, 12, 18 and 24 weeks was calculated based on the number of subjects with a value at each time point in High Glycemic Group.	Baseline, up to 24 weeks

Collaborators and Investigators

• Sponsor: Theracos
• Investigators: Study Director: J, Paul Lock, M.D., Theracos

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 28, 2017
• Primary Completion (ACTUAL): January 23, 2019
• Study Completion (ACTUAL): January 23, 2019

Study Registration Dates

• First Submitted: August 21, 2017
• First Submitted That Met QC Criteria: August 21, 2017
• First Posted (ACTUAL): August 24, 2017

Study Record Updates

• Last Update Posted (ACTUAL): July 7, 2021
• Last Update Submitted That Met QC Criteria: July 6, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Bexagliflozin
• Other Study ID Numbers: THR-1442-C-419

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No