Type 2 Diabetes Mellitus
Conditions
Brief summary
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
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.
Interventions
DRUGBexagliflozin
20 mg, tablet
inactive tablet to match active comparator bexagliflozin
DRUGGlimepiride
2, 4 or 6 mg, capsule
inactive capsules to match active comparator glimepiride
Sponsors
Theracos
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c at Week 60 | Baseline and 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Body Weight at Week 60 for Subjects With Baseline BMI ≥ 25 kg/m2 | Baseline and 60 weeks | 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. |
| Change From Baseline in Systolic Blood Pressure (SBP) at Week 60 for Subjects With Baseline SBP ≥ 140 mmHg | Baseline and 60 weeks | 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. |
| Difference in Proportion of Subjects With ≥ 1 Severe or Documented Symptomatic Hypoglycemia Events Over 96 Weeks | During the 96 week treatment period | 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. |
| Superiority of Bexagliflozin Over Glimepiride in HbA1c Reduction at Week 60. | Baseline to 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. |
Countries
Germany, Poland, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bexagliflozin 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 for the duration of the study.
Bexagliflozin tablets: 20 mg
Glimepiride capsules: Placebo, inactive capsule to match the active comparator | 213 |
| Glimepiride 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.
Bexagliflozin: Placebo, inactive tablet to match the active comparator
Glimepiride capsules: 2, 4 or 6 mg | 213 |
| Total | 426 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 6 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Entry Criteria Not Met | 1 | 2 |
| Overall Study | Lost to Follow-up | 9 | 9 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Terminated by Sponsor | 1 | 0 |
| Overall Study | Undefined | 4 | 1 |
| Overall Study | Withdrawal by Subject | 14 | 16 |
Baseline characteristics
| Characteristic | Glimepiride | Bexagliflozin | Total |
|---|---|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 10.35 | 59.5 years STANDARD_DEVIATION 9.06 | 59.6 years STANDARD_DEVIATION 9.71 |
| BMI | 32.22 kg/m^2 STANDARD_DEVIATION 5.155 | 31.45 kg/m^2 STANDARD_DEVIATION 4.861 | 31.83 kg/m^2 STANDARD_DEVIATION 5.019 |
| Body Weight at Baseline | 90.23 kg STANDARD_DEVIATION 17.616 | 87.95 kg STANDARD_DEVIATION 19.122 | 89.09 kg STANDARD_DEVIATION 18.399 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 47 Participants | 46 Participants | 93 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 166 Participants | 167 Participants | 333 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 167.1 cm STANDARD_DEVIATION 9.53 | 166.7 cm STANDARD_DEVIATION 11.13 | 166.9 cm STANDARD_DEVIATION 10.35 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 9 Participants | 13 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 204 Participants | 198 Participants | 402 Participants |
| Region of Enrollment Germany | 29 participants | 28 participants | 57 participants |
| Region of Enrollment Poland | 79 participants | 74 participants | 153 participants |
| Region of Enrollment Spain | 42 participants | 46 participants | 88 participants |
| Region of Enrollment United States | 63 participants | 65 participants | 128 participants |
| Sex: Female, Male Female | 83 Participants | 95 Participants | 178 Participants |
| Sex: Female, Male Male | 130 Participants | 118 Participants | 248 Participants |
| Systolic Blood Pressure at Baseline | 134.2 mm Hg STANDARD_DEVIATION 14.37 | 133.3 mm Hg STANDARD_DEVIATION 14.88 | 133.8 mm Hg STANDARD_DEVIATION 14.62 |
| Systolic Blood Pressure Categories < 140 mm Hg | 138 Participants | 135 Participants | 273 Participants |
| Systolic Blood Pressure Categories > 140 mm Hg | 75 Participants | 78 Participants | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 213 | 1 / 213 |
| other Total, other adverse events | 98 / 213 | 112 / 213 |
| serious Total, serious adverse events | 25 / 213 | 26 / 213 |
Outcome results
Primary
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).
Time frame: Baseline and Week 60
Population: The intention-to-treat population was used for the analysis. Subjects with a value at baseline and at week 60 were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin | Change From Baseline in HbA1c at Week 60 | -0.70 percentage of glycated hemoglin | Standard Error 0.058 |
| Glimepiride | Change From Baseline in HbA1c at Week 60 | -0.66 percentage of glycated hemoglin | Standard Error 0.058 |
Comparison: The null hypothesis for the primary endpoint was that the change in HbA1c from baseline to week 60 in the bexagliflozin arm would be greater than change in the glimepiride arm by greater than 0.35%.95% CI: [-0.21, 0.11]
Secondary
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.
Time frame: Baseline and 60 weeks
Population: Number of subjects with a value at baseline and at the specified visit
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin | Change From Baseline in Body Weight at Week 60 for Subjects With Baseline BMI ≥ 25 kg/m2 | -3.71 kg | Standard Error 0.285 |
| Glimepiride | Change From Baseline in Body Weight at Week 60 for Subjects With Baseline BMI ≥ 25 kg/m2 | 0.59 kg | Standard Error 0.284 |
p-value: <0.000195% CI: [-5.1, -3.52]Mixed-effects repeated measures
Secondary
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.
Time frame: Baseline and 60 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin | Change From Baseline in Systolic Blood Pressure (SBP) at Week 60 for Subjects With Baseline SBP ≥ 140 mmHg | -13.48 mm Hg | Standard Error 1.404 |
| Glimepiride | Change From Baseline in Systolic Blood Pressure (SBP) at Week 60 for Subjects With Baseline SBP ≥ 140 mmHg | -6.95 mm Hg | Standard Error 1.46 |
p-value: 0.000895% CI: [-10.56, -2.51]Mixed-effects repeated measures
Secondary
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.
Time frame: During the 96 week treatment period
Population: Subjects with post-baseline assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bexagliflozin | Difference in Proportion of Subjects With ≥ 1 Severe or Documented Symptomatic Hypoglycemia Events Over 96 Weeks | 0.02 Proportion of participants |
| Glimepiride | Difference in Proportion of Subjects With ≥ 1 Severe or Documented Symptomatic Hypoglycemia Events Over 96 Weeks | 0.15 Proportion of participants |
p-value: <0.000195% CI: [0.05, 0.28]Regression, Logistic
Secondary
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.
Time frame: Baseline to Week 60
Population: The intention-to-treat population was used for the analysis. Subjects with a value at baseline and at week 60 were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin | Superiority of Bexagliflozin Over Glimepiride in HbA1c Reduction at Week 60. | -0.70 percentage of glycated hemoglobin | Standard Error 0.058 |
| Glimepiride | Superiority of Bexagliflozin Over Glimepiride in HbA1c Reduction at Week 60. | -0.66 percentage of glycated hemoglobin | Standard Error 0.058 |
95% CI: [-0.21, 0.11]