Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of this study is to investigate the effect of bexagliflozin in lowering hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM).
Detailed description
This was a phase 3, multi-center, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of once daily oral administration of bexagliflozin tablets, 20 mg or placebo tablets, in male and female subjects with T2DM who were treatment-naïve or previously treated with 1 oral hypoglycemic agent (OHA). Prospective subjects being treated with one OHA were eligible if they had an HbA1c between 6.5% and 10.0% and were willing to complete a 6-week washout. Individuals taking thiazolidinediones were not eligible for the study. All eligible subjects were to start a 2-week placebo run-in period. Subjects who missed no more than 1 dose of the run-in medication, had fasting blood glucose values ≥ 250 mg/dL on no more than two consecutive days, and had an HbA1c level between 7.0% and 10.5% and a fasting glucose level \< 250 mg/dL after the run-in period were eligible for randomization. Two hundred and ten (210) subjects were planned to be randomly assigned to receive oral bexagliflozin tablets, 20 mg or placebo, in a 2:1 ratio once daily for 24 weeks. Subjects with uncontrolled hyperglycemia based on blood glucose levels could receive additional approved anti-diabetic medications. Treatment group assignment at the start of the treatment period was stratified by baseline HbA1c level and background anti-diabetes treatment status (treatment naïve or not). Each subject was contacted by telephone at week 2 and was instructed to return to the clinic at weeks 6, 12, 18, and 24 for efficacy assessment and safety monitoring. Subjects returned to the clinic for a follow-up visit at week 26 or 2 weeks after the last dose of investigational product if the subject terminated prior to week 24.
Interventions
DRUGBexagliflozin
tablets containing 20 mg bexagliflozin
DRUGPlacebo
tablets matching the appearance of bexagliflozin tablets
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
The study population included: 1. Male or female adult subjects ≥ 18 years of age at screening 2. Subjects who were treatment naïve or receiving 1 OHA in combination with diet and exercise 3. Subjects with a diagnosis of T2DM 4. Subjects with HbA1c levels at screening between 7.0% and 10.5% (inclusive) if treatment-naïve or with HbA1c levels between 6.5 and 10.0% (inclusive) if on 1 oral anti diabetic agent 5. Subjects with a BMI ≤ 45 kg/m2 6. Subjects whose doses of medications for hypertension or hyperlipidemia (if applicable) had not changed for at least 30 days prior to screening 7. Subjects who were willing and able to return for all clinic visits and to complete all study required procedures 8. Female subjects of childbearing potential who were willing to use an adequate method of contraception and not become pregnant for the duration of the study. 9. Subjects who maintained glycemic control throughout washout, if applicable. 10. Subjects who had HbA1c levels between 7.0 and 10.5% prior to randomization 11. Subjects who had been compliant in investigational product administration by missing no more than 1 dose of run-in medication Subjects who met any of the following criteria were excluded from the study: 1. A diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young 2. Use of injected therapy for treatment of diabetes (insulin or GLP-1 receptor agonist therapy) or thiazolidinedione class drugs at the time of screening 3. Female subjects who were pregnant or breastfeeding 4. Hemoglobinopathy or carrier status for hemoglobin alleles that affected HbA1c measurement 5. Genitourinary tract infection (e.g., UTI, GMI, vaginitis, balanitis) within 6 weeks of screening or history of ≥ 3 genitourinary infections requiring treatment within 6 months from screening 6. Estimated glomerular filtration rate (eGFR), as calculated by the modification of diet in renal disease study equation (MDRD), \< 60 mL/min/1.73 m2 at screening 7. Uncontrolled hypertension defined as a sitting systolic blood pressure \>160 mm Hg or diastolic blood pressure \> 95 mm Hg at screening 8. A positive result for hepatitis B surface antigen (HBsAg) or hepatitis C (HCV) 9. History of alcohol or illicit drug abuse in the past 2 years 10. Known human immunodeficiency virus (HIV) positive based on medical history 11. Life expectancy \< 2 years 12. New York Heart Association (NYHA) Class IV heart failure within 3 months of screening 13. MI, unstable angina, stroke, or hospitalization for heart failure within 3 months of screening 14. Treatment with an investigational drug within 30 days or within 7 half-lives of the investigational drug, whichever was longer 15. Previous treatment with bexagliflozin or EGT0001474 16. Use of any SGLT2 inhibitors, either at the time of screening or in the prior 3 months 17. Currently participating in another interventional trial 18. Not able to comply with the study scheduled visits 19. 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 20. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 x ULN or total bilirubin ≥ 1.5 x upper limit of normal (ULN) with the exception of isolated Gilbert's syndrome at screening 21. Two or more consecutive FPG measures ≥ 250 mg/dL (13.9 mmol/L) prior to randomization or 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 22. At last visit prior to randomization, FPG level ≥ 250 mg/dL 23. Prior renal transplantation or evidence of nephrotic syndrome (defined as a urine albumin-to-creatinine ratio (UACR) \> 2000 mg/g at screening).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline at Week 24 | 24 weeks | Glycated hemoglobin A1c (%) was measured using an HPLC method in the laboratories that had completed NGSP Level I laboratory certification and were traceable to the Diabetes Control and Complications Trial (DCCT) reference method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Systolic Blood Pressure (SBP) From Baseline at Week 24 | 24 weeks | Blood pressure (BP) measurements are obtained using a calibrated sphygmomanometer in sitting, supine and standing positions. The left arm and same cuff sizes should be used for each measurement at all visits. If the left arm cannot be used at the screening visit or during the study for BP measurements, the reason should be documented and the right arm should be used for BP measurements for all subsequent visits. |
| Change in Body Weight From Baseline at Week 24 in Subjects With a BMI ≥ 25 Kg/m2 | 24 weeks | The body weight was obtained using a calibrated scale as part of complete physical examination or abbreviated physical examination. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) Over Time | 24 weeks | The fasting plasma glucose (FPG) is measured at each study visit. The subject must have fasted for approximately 10 hours prior to the blood draw to ensure that the FPG value is truly a fasting sample. |
| Change From Baseline of HbA1c From Baseline Over Time | 24 weeks | Glycated hemoglobin A1c (%) was measured using an HPLC method in the laboratories that had completed NGSP Level I laboratory certification and were traceable to the Diabetes Control and Complications Trial (DCCT) reference method. |
| Proportion of Subjects Who Achieve an HbA1c < 7% | Up to 24 weeks | Glycated hemoglobin A1c (%) was measured using an HPLC method in the laboratories that had completed NGSP Level I laboratory certification and were traceable to the Diabetes Control and Complications Trial (DCCT) reference method. |
Countries
Canada, United States
Participant flow
Pre-assignment details
A total of 210 subjects were randomized to be in the bexagliflozin arm or in the placebo arm in a ratio of 2:1.
Participants by arm
| Arm | Count |
|---|---|
| Bexagliflozin Tablets, 20 mg Each subject will receive bexagliflozin tablets, 20 mg once daily for 24 weeks. | 138 |
| Placebo Tablets Each subject will receive placebo (inactive tablet) once daily for 24 weeks. | 69 |
| Total | 207 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | GCP violation | 2 | 1 |
| Overall Study | Lost to Follow-up | 7 | 1 |
| Overall Study | Subject non-compliant | 1 | 1 |
| Overall Study | Terminated by Sponsor | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 1 |
Baseline characteristics
| Characteristic | Placebo Tablets | Bexagliflozin Tablets, 20 mg | Total |
|---|---|---|---|
| Age, Continuous | 54.7 years STANDARD_DEVIATION 11.02 | 55.8 years STANDARD_DEVIATION 10.21 | 55.4 years STANDARD_DEVIATION 10.47 |
| Body Mass Index | 30.48 kg/m^2 STANDARD_DEVIATION 4.65 | 32.79 kg/m^2 STANDARD_DEVIATION 5.653 | 32.01 kg/m^2 STANDARD_DEVIATION 5.437 |
| Body Weight at Baseline | 84.6 kg STANDARD_DEVIATION 19.75 | 90.5 kg STANDARD_DEVIATION 20.48 | 88.6 kg STANDARD_DEVIATION 20.39 |
| Duration of Diabetes from Diagnosis to Screening | 6.5 years STANDARD_DEVIATION 5.21 | 5.9 years STANDARD_DEVIATION 5.82 | 6.1 years STANDARD_DEVIATION 5.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 40 Participants | 67 Participants | 107 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 71 Participants | 100 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Fasting Plasma Glucose (FPG) | 9.45 mmol/L STANDARD_DEVIATION 2.079 | 9.39 mmol/L STANDARD_DEVIATION 1.957 | 9.41 mmol/L STANDARD_DEVIATION 1.994 |
| HbA1c | 7.97 percentage of glycated hemoglobin STANDARD_DEVIATION 0.757 | 8.05 percentage of glycated hemoglobin STANDARD_DEVIATION 0.824 | 8.02 percentage of glycated hemoglobin STANDARD_DEVIATION 0.801 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 15 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 25 Participants | 31 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 | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 58 Participants | 96 Participants | 154 Participants |
| Region of Enrollment Canada | 12 participants | 21 participants | 33 participants |
| Region of Enrollment United States | 57 participants | 117 participants | 174 participants |
| Sex: Female, Male Female | 35 Participants | 72 Participants | 107 Participants |
| Sex: Female, Male Male | 34 Participants | 66 Participants | 100 Participants |
| Systolic Blood Pressure | 125.6 mmHg STANDARD_DEVIATION 13.84 | 131.0 mmHg STANDARD_DEVIATION 14.35 | 129.2 mmHg STANDARD_DEVIATION 14.38 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 138 | 1 / 69 |
| other Total, other adverse events | 41 / 138 | 25 / 69 |
| serious Total, serious adverse events | 1 / 138 | 1 / 69 |
Outcome results
Primary
Change in HbA1c From Baseline at Week 24
Glycated hemoglobin A1c (%) was measured using an HPLC method in the laboratories that had completed NGSP Level I laboratory certification and were traceable to the Diabetes Control and Complications Trial (DCCT) reference method.
Time frame: 24 weeks
Population: Intention-to-Treat Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin Tablets, 20 mg | Change in HbA1c From Baseline at Week 24 | -0.51 % of HbA1c | Standard Error 0.082 |
| Placebo Tablets | Change in HbA1c From Baseline at Week 24 | -0.10 % of HbA1c | Standard Error 0.108 |
Comparison: Analysis of change from baseline in HbA1c (%) at Week 24p-value: 0.001295% CI: [-0.66, -0.16]Mixed Models Analysis
Comparison: Sensitivity Analysis 1: Multiple imputation for change from baseline in HbA1c (%) including observations obtained after rescue medicationp-value: 0.002195% CI: [-0.68, -0.15]ANCOVA
Comparison: Sensitivity Analysis 2: Multiple imputation for change from baseline in HbA1c (%) excluding observations obtained after rescue medicationp-value: <0.000195% CI: [-0.8, -0.3]Mixed Models Analysis
Comparison: Sensitivity Analysis 3: LOCF for change from baseline in HbA1c (%) including observations obtained after rescue medicationp-value: 0.000995% CI: [-0.64, -0.17]ANCOVA
Secondary
Change in Body Weight From Baseline at Week 24 in Subjects With a BMI ≥ 25 Kg/m2
The body weight was obtained using a calibrated scale as part of complete physical examination or abbreviated physical examination.
Time frame: 24 weeks
Population: Subjects with BMI \>= 25 kg/m2 in the ITT analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin Tablets, 20 mg | Change in Body Weight From Baseline at Week 24 in Subjects With a BMI ≥ 25 Kg/m2 | -1.85 Kg | Standard Error 0.394 |
| Placebo Tablets | Change in Body Weight From Baseline at Week 24 in Subjects With a BMI ≥ 25 Kg/m2 | -1.06 Kg | Standard Error 0.485 |
Comparison: Analysis of change from baseline in body weight (kg) at Week 24 for subjects with BMI greater than or equal to 25 kg/m2p-value: 0.122295% CI: [-1.8, 0.21]ANCOVA
Comparison: Sensitivity Analysis 1: Multiple imputation for change from baseline in body weight (kg) for subjects with BMI greater than or equal to 25 kg/m2 including observations obtained after rescue medicationp-value: 0.201495% CI: [-1.65, 0.35]ANCOVA
Comparison: Sensitivity Analysis 2: Multiple imputation for change from baseline in body weight (kg) for subjects with BMI greater than or equal to 25 kg/m2 excluding observations obtained after rescue medicationp-value: 0.063895% CI: [-1.88, 0.05]ANCOVA
Comparison: Sensitivity Analysis 3: LOCF for change from baseline in body weight (kg) for subjects with BMI greater than or equal to 25 kg/m2 including observations obtained after rescue medicationp-value: 0.145695% CI: [-1.63, 0.24]ANCOVA
Secondary
Change in Systolic Blood Pressure (SBP) From Baseline at Week 24
Blood pressure (BP) measurements are obtained using a calibrated sphygmomanometer in sitting, supine and standing positions. The left arm and same cuff sizes should be used for each measurement at all visits. If the left arm cannot be used at the screening visit or during the study for BP measurements, the reason should be documented and the right arm should be used for BP measurements for all subsequent visits.
Time frame: 24 weeks
Population: ITT analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin Tablets, 20 mg | Change in Systolic Blood Pressure (SBP) From Baseline at Week 24 | -0.60 mmHg | Standard Error 1.145 |
| Placebo Tablets | Change in Systolic Blood Pressure (SBP) From Baseline at Week 24 | 1.54 mmHg | Standard Error 1.524 |
Comparison: Analysis of change from baseline in SBP (mm Hg) at Week 24p-value: 0.23495% CI: [-5.66, 1.39]ANCOVA
Comparison: Sensitivity Analysis 1: Multiple imputation for change from baseline in SBP (mm Hg) including observations obtained after rescue medicationp-value: 0.293795% CI: [-5.48, 1.66]ANCOVA
Comparison: Sensitivity Analysis 2: Multiple imputation for change from baseline in SBP (mm Hg) excluding observations obtained after rescue medicationp-value: 0.40395% CI: [-5.75, 2.32]ANCOVA
p-value: 0.21695% CI: [-5.41, 1.23]ANCOVA
Other Pre-specified
Change From Baseline in Fasting Plasma Glucose (FPG) Over Time
The fasting plasma glucose (FPG) is measured at each study visit. The subject must have fasted for approximately 10 hours prior to the blood draw to ensure that the FPG value is truly a fasting sample.
Time frame: 24 weeks
Population: Subjects with a value at baseline and Week 6, 12, 18 and 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bexagliflozin Tablets, 20 mg | Change From Baseline in Fasting Plasma Glucose (FPG) Over Time | Change from baseline at Week 6 | -1.40 mmol/L | Standard Deviation 2.116 |
| Bexagliflozin Tablets, 20 mg | Change From Baseline in Fasting Plasma Glucose (FPG) Over Time | Change from baseline at Week 12 | -1.41 mmol/L | Standard Deviation 1.904 |
| Bexagliflozin Tablets, 20 mg | Change From Baseline in Fasting Plasma Glucose (FPG) Over Time | Change from baseline at Week 18 | -1.17 mmol/L | Standard Deviation 2.058 |
| Bexagliflozin Tablets, 20 mg | Change From Baseline in Fasting Plasma Glucose (FPG) Over Time | Change from baseline at Week 24 | -1.02 mmol/L | Standard Deviation 2.013 |
| Placebo Tablets | Change From Baseline in Fasting Plasma Glucose (FPG) Over Time | Change from baseline at Week 24 | -0.15 mmol/L | Standard Deviation 2.48 |
| Placebo Tablets | Change From Baseline in Fasting Plasma Glucose (FPG) Over Time | Change from baseline at Week 6 | 0.50 mmol/L | Standard Deviation 2.655 |
| Placebo Tablets | Change From Baseline in Fasting Plasma Glucose (FPG) Over Time | Change from baseline at Week 18 | 0.03 mmol/L | Standard Deviation 2.337 |
| Placebo Tablets | Change From Baseline in Fasting Plasma Glucose (FPG) Over Time | Change from baseline at Week 12 | 0.33 mmol/L | Standard Deviation 2.103 |
Comparison: Analysis of change from baseline in FPG (mmol/L) over time across 24 weeksp-value: <0.000195% CI: [-1.92, -1.09]ANCOVA
Other Pre-specified
Change From Baseline of HbA1c From Baseline Over Time
Glycated hemoglobin A1c (%) was measured using an HPLC method in the laboratories that had completed NGSP Level I laboratory certification and were traceable to the Diabetes Control and Complications Trial (DCCT) reference method.
Time frame: 24 weeks
Population: Subjects with a value at baseline and at Week 6, 12, 18 and 24
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Bexagliflozin Tablets, 20 mg | Change From Baseline of HbA1c From Baseline Over Time | Change from baseline at Week 6 | -0.47 % of HbA1c | Standard Error 0.064 |
| Bexagliflozin Tablets, 20 mg | Change From Baseline of HbA1c From Baseline Over Time | Change from baseline at Week 12 | -0.61 % of HbA1c | Standard Error 0.072 |
| Bexagliflozin Tablets, 20 mg | Change From Baseline of HbA1c From Baseline Over Time | Change from baseline at Week 18 | -0.58 % of HbA1c | Standard Error 0.071 |
| Bexagliflozin Tablets, 20 mg | Change From Baseline of HbA1c From Baseline Over Time | Change from baseline at Week 24 | -0.51 % of HbA1c | Standard Error 0.082 |
| Placebo Tablets | Change From Baseline of HbA1c From Baseline Over Time | Change from baseline at Week 24 | -0.10 % of HbA1c | Standard Error 0.108 |
| Placebo Tablets | Change From Baseline of HbA1c From Baseline Over Time | Change from baseline at Week 6 | 0.13 % of HbA1c | Standard Error 0.082 |
| Placebo Tablets | Change From Baseline of HbA1c From Baseline Over Time | Change from baseline at Week 18 | -0.01 % of HbA1c | Standard Error 0.093 |
| Placebo Tablets | Change From Baseline of HbA1c From Baseline Over Time | Change from baseline at Week 12 | 0.10 % of HbA1c | Standard Error 0.095 |
Comparison: Change from baseline in HbA1c (%) at Week 6p-value: <0.000195% CI: [-0.79, -0.43]ANCOVA
Comparison: Change from baseline in HbA1c (%) at Week 12p-value: <0.000195% CI: [-0.92, -0.5]ANCOVA
Comparison: Change from baseline in HbA1c (%) at Week 18p-value: <0.000195% CI: [-0.78, -0.36]ANCOVA
Comparison: Change from baseline in HbA1c (%) at Week 24p-value: 0.001295% CI: [-0.66, -0.16]ANCOVA
Comparison: Change from baseline in HbA1c (%) across 24 weeksp-value: <0.000195% CI: [-0.76, -0.39]ANCOVA
Other Pre-specified
Proportion of Subjects Who Achieve an HbA1c < 7%
Glycated hemoglobin A1c (%) was measured using an HPLC method in the laboratories that had completed NGSP Level I laboratory certification and were traceable to the Diabetes Control and Complications Trial (DCCT) reference method.
Time frame: Up to 24 weeks
Population: Subjects with a value at baseline and at Week 6, 12, 18 and 24
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bexagliflozin Tablets, 20 mg | Proportion of Subjects Who Achieve an HbA1c < 7% | Proportion of subjects with HbA1c < 7% at Week 12 | 44 participants |
| Bexagliflozin Tablets, 20 mg | Proportion of Subjects Who Achieve an HbA1c < 7% | Proportion of subjects with HbA1c < 7% at Week 6 | 35 participants |
| Bexagliflozin Tablets, 20 mg | Proportion of Subjects Who Achieve an HbA1c < 7% | Proportion of subjects with HbA1c < 7% at Week 18 | 42 participants |
| Bexagliflozin Tablets, 20 mg | Proportion of Subjects Who Achieve an HbA1c < 7% | Proportion of subjects with HbA1c < 7% at Week 24 | 41 participants |
| Placebo Tablets | Proportion of Subjects Who Achieve an HbA1c < 7% | Proportion of subjects with HbA1c < 7% at Week 24 | 13 participants |
| Placebo Tablets | Proportion of Subjects Who Achieve an HbA1c < 7% | Proportion of subjects with HbA1c < 7% at Week 6 | 6 participants |
| Placebo Tablets | Proportion of Subjects Who Achieve an HbA1c < 7% | Proportion of subjects with HbA1c < 7% at Week 12 | 8 participants |
| Placebo Tablets | Proportion of Subjects Who Achieve an HbA1c < 7% | Proportion of subjects with HbA1c < 7% at Week 18 | 10 participants |
Comparison: Model-Adjusted proportion of subjects with HbA1c \<7% across 24 weeksp-value: 0.000695% CI: [1.69, 6.8]ANCOVA