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

• ClinicalTrials.gov Identifier: NCT03259789
• Recruitment Status: Completed
• First Posted: August 24, 2017
• Results First Posted: July 7, 2021
• Last Update Posted: July 7, 2021
• Sponsor: Theracos
• Information provided by (Responsible Party): Theracos

Tracking Information

• First Submitted Date: August 21, 2017
• First Posted Date: August 24, 2017
• Results First Submitted Date: April 5, 2021
• Results First Posted Date: July 7, 2021
• Last Update Posted Date: July 7, 2021
• Actual Study Start Date: November 28, 2017
• Actual Primary Completion Date: January 23, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 20, 2021)

• Change From Baseline in HbA1c at Week 24 for Double-blind Group [ Time Frame: Baseline to week 24 ]
  HbA1c was obtained at baseline and at Week 24. The model-adjusted change from baseline was calculated using mixed-effects repeated measures analysis.
• Change From Baseline in HbA1c at Week 24 for High Glycemic Group [ Time Frame: Baseline to week 24 ]
  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

• Original Primary Outcome Measures (submitted: August 21, 2017): Change in HbA1c from baseline to week 24 [ Time Frame: Baseline and 24 weeks ]

Current Secondary Outcome Measures (submitted: May 20, 2021)

• Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 for Double-blind Group [ Time Frame: Baseline, up to 24 weeks ]
  FPG was obtained at baseline and at Week 24. The model-adjusted change from baseline was calculated using mixed-effects repeated measures analysis.
• Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 for High Glycemic Group [ Time Frame: Baseline, up to 24 weeks ]
  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
• Change From Baseline in Systolic Blood Pressure (SBP) at Week 24 [ Time Frame: Baseline to week 24 ]
  Changes from baseline at Week 24 in SBP for the double-blind group and high glycemic group
• Proportion of Subjects Achieving HbA1c < 7% Over Time for Double-blind Group [ Time Frame: Baseline, up to 24 weeks ]
  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.
• Proportion of Subjects Achieving HbA1c < 7% Over Time for High Glycemic Group [ Time Frame: Baseline, up to 24 weeks ]
  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.
• Change in Body Mass From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2 for Double-blind Group [ Time Frame: Baseline to week 24 ]
  Changes in body mass from baseline to week 24 was calculated based on LS means for both bexagliflozin and placebo groups.
• Change in Body Mass From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2 for High Glycemic Group [ Time Frame: Baseline to week 24 ]
  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
• Change From Baseline in HbA1c Over Time in Double-blind Treatment Group [ Time Frame: Baseline, up to 24 weeks ]
  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.
• Change in HbA1c Over Time Among Subjects Who Have Baseline HbA1c of > 10.5% and ≤ 12.0% [ Time Frame: Baseline, up to 24 weeks ]
  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.

Original Secondary Outcome Measures (submitted: August 21, 2017)

• Change in FPG over time [ Time Frame: Baseline, up to 24 weeks ]
• Change in SBP over time [ Time Frame: Baseline, up to 24 weeks ]
• Proportion of subjects achieving HbA1c of≤ 7% over time [ Time Frame: Baseline, up to 24 weeks ]
• Change in total body weight in subjects with baseline BMI ≥ 25 kg/m2 over time [ Time Frame: Baseline, up to 24 weeks ]
• Change in HbA1c over time [ Time Frame: Baseline, up to 24 weeks ]
• Change in HbA1c among subjects who have baseline HbA1c of > 10.5% and ≤ 12.0% over time [ Time Frame: Baseline, up to 24 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: August 21, 2017)

• Safety of exposure to bexagliflozin for 24 weeks as assessed by analyzing treatment emergent adverse events, laboratory results, electrocardiogram parameters, physical examinations, vital signs and use of concomitant medications [ Time Frame: Baseline, up to 24 weeks ]
• Bexagliflozin plasma concentrations over time [ Time Frame: Baseline, week 6 and 12 ]

Descriptive Information

• Brief Title: Safety and Efficacy of Bexagliflozin Compared to Placebo as Add-on Therapy to Metformin in Type 2 Diabetes Subjects
• Official Title: 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
• Brief Summary: 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).
• 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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Type2 Diabetes Mellitus

Intervention

• Drug: Bexagliflozin tablets, 20 mg
  Each subject will receive bexagliflozin, 20 mg once daily for the duration of the study.
  Other Name: EGT0001442, EGT0001474
• Drug: Bexagliflozin tablets, placebo
  Each subject will receive placebo (inactive tablet) once daily for the duration of the study.

Study Arms

• Active Comparator: Bexagliflozin tablets, 20 mg; Double-Blind
  Intervention: Drug: Bexagliflozin tablets, 20 mg
• Placebo Comparator: Bexagliflozin tablets, Placebo; Double Blind
  Intervention: Drug: Bexagliflozin tablets, placebo
• Experimental: Bexagliflozin Tablets, 20 mg; High Glycemic Group
  Intervention: Drug: Bexagliflozin tablets, 20 mg

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 5, 2021): 351
• Original Estimated Enrollment (submitted: August 21, 2017): 350
• Actual Study Completion Date: January 23, 2019
• Actual Primary Completion Date: January 23, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 20 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan, United States

Administrative Information

• NCT Number: NCT03259789
• Other Study ID Numbers: THR-1442-C-419
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Theracos
• Original Responsible Party: Same as current
• Current Study Sponsor: Theracos
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Theracos
• Verification Date: July 2021