Type 2 Diabetes Mellitus
Conditions
Brief summary
This was a phase 3, multi-center, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of oral administration of bexagliflozin at 20 mg versus placebo in subjects with T2DM, moderate renal impairment and inadequate glycemic control.
Detailed description
The phase 3, double-blind, placebo-controlled parallel-group study was conducted at investigative sites in the US, Japan, France and Spain. Approximately 300 subjects were to be randomly assigned to receive bexagliflozin tablets, 20 mg, or placebo in equal ratio for 24 weeks. The study was to enrolled male and female participants who had T2DM with an HbA1c between 7.0 and 10.5% (inclusive) and stage 3 chronic kidney disease (CKD) as defined by an eGFR of ≥ 30 and\< 60 mL min-1 per 1.73 m2 at the screening visit and one additional time of measurement between 1 and 12 months prior to screening. Subjects were either treatment naïve or were treated with a stable regimen of anti-diabetic medications. All eligible subjects were to enter a one-week single-blind, placebo run-in period. Subjects who were compliant in taking run-in medication, had screening eGFR ≥ 30 and\< 60 mL min-1 per 1.73 m2, and had stable GFR (no more than 20% change in eGFR between a historical value and the value determined at the screening visit) were eligible for randomization. Randomization was stratified by HbA1c level (7.0 to 8.5% or 8.6 to 10.5%), anti-diabetic treatment regimen and eGFR (30 - 44 mL min-1 per 1.73 m2 or 45 - 59 mL min-1 per 1.73 m2). At least 135 subjects in each of the eGFR groups were planned. Study subjects were to schedule clinic visits at weeks 2, 6, 12, 18, and 24 for safety and efficacy evaluation. At weeks 2 and 18, the visits were to be conducted via phone interviews unless an in-person visit was considered clinically advisable. A final follow-up visit was to be conducted at week 26 or two weeks after the last dose of investigational product if the subject withdrew prior to week 24.
Interventions
DRUGBexagliflozin
Bexagliflozin tablet, 20 mg
DRUGPlacebo
Placebo (inactive) tablet to match the active comparator
Sponsors
Theracos
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each subject was required to meet the following criteria at the time of enrollment to be eligible for the study: 1. To have been male or non-pregnant female ≥ 20 years of age. Women of childbearing potential were required to agree to use contraception throughout the study to avoid any possible pregnancy. Females who were surgically sterile (hysterectomy, oophorectomy) or postmenopausal (absence of menses for greater than 12 months and age \> 45 years) were eligible if they tested negative on the urine pregnancy test. 2. To have had a diagnosis of T2DM with an HbA1c between 7.0 and 10.5% (inclusive) at the time of screening. 3. To have been treatment naïve or to have been treated with a stable regimen of anti-diabetic medications. At the time of screening, the doses and frequency of all anti-diabetic medications were to have been stable for 8 weeks. 4. To have had an eGFR ≥ 30 and \< 60 mL min-1 per 1.73 m2 at 2 time points: screening (V1), and 1 additional time point between 1 and 12 months of screening (may be obtained from available medical records). The eGFR was calculated by the MDRD equation. 5. To have had a body mass index (BMI) ≤ 45 kg per m2 (inclusive). 6. To have been taking stable doses of medications for hypertension or hyperlipidemia (if applicable) for at least 30 days prior to randomization 7. To have had stable eGFR between the historic value and day of screening (no more than 20% change in eGFR between the most recent historical value and the value determined at the screening visit V1). 9.3.2
Exclusion criteria
Potential participants who exhibited any of the following characteristics were excluded from the study: 1. A diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young (MODY) 2. A hemoglobinopathy that could affect HbA1c measurement 3. Frequent symptomatic hypoglycemia (greater than one episode per week on average) 4. A history of genitourinary tract infection within 6 weeks of screening or history of ≥ 3 genitourinary infections requiring treatment within the last 6 months 5. A cancer, active or in remission for \< 3 years (Non-melanoma skin cancer or basal cell carcinoma or carcinoma in situ of the cervix were not grounds for exclusion) 6. A history of alcohol or illicit drug abuse in the past 2 years 7. Evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase \> 1.5 × upper limit of normal (ULN) with the exception of isolated Gilbert's syndrome); or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.5 × ULN 8. A history of MI, stroke or hospitalization for heart failure, or hospitalization for unstable angina in the prior 3 months 9. Evidence of NYHA class IV heart failure at screening or randomization 10. A history of taking an SGLT2 inhibitor within 3 months of screening 11. Any condition, disease, disorder, or clinically relevant laboratory abnormality that, in the opinion of the PI, would jeopardize the subject's appropriate participation in this study or obscure the effects of treatment 12. A current status of pregnancy or breastfeeding 13. A current status of renal replacement therapy (peritoneal or hemodialysis) or a history of renal transplantation 14. A corrected serum calcium \< 8 mg dL-1 at screening (V1) or randomization (V3) 15. Uncontrolled hypertension (systolic blood pressure \>170 mm Hg or diastolic blood pressure \>110 mm Hg) 16. Participation in another interventional trial or exposure to an investigational drug within 30 days or 7 half-lives of screening, whichever was longer 17. Previous exposure to bexagliflozin or EGT0001474 18. Evidence of having skipped dosing more than once during the run-in period 19. A fasting blood glucose value during the run-in period ≥ 250 mg dL-1 (13.9 mmol L-1) associated with severe clinical signs or symptoms of hyperglycemia 20. Any episode of symptomatic hypoglycemia during the run-in period in which symptoms were severe 21. An inability to comprehend or unwillingness to provide written informed consent in accordance with institutional and regulatory guidelines
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c at 24 Weeks | 24 weeks | The primary efficacy objective of this trial is to evaluate the placebo-adjusted change in HbA1c from baseline after 24 weeks of treatment with 20 mg bexagliflozin tablets in type 2 diabetic subjects with moderate renal impairment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Weight From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2 | 24 weeks | A secondary objective is to evaluate the effect of bexagliflozin 20 mg on the placebo-adjusted change in BMI from baseline to week 24 in subjects with a BMI ≥ 25 kg/m2. |
| Change From Baseline in Systolic Blood Pressure (SBP) in Subjects With Baseline SBP ≥ 130 mm Hg at Week 24 | 24 weeks | A secondary objective is to evaluate the effect of bexagliflozin 20 mg on the placebo-adjusted change from baseline in SBP to in subjects with baseline SBP ≥ 130 mm Hg at Week 24. |
| Change From Baseline in HbA1c in Subjects With Stage 3a CKD (eGFR 45 to 59 mL/Min/1.73 m2) at Week 24 | 24 weeks | A secondary objective is to evaluate the effect of bexagliflozin 20 mg on the placebo-adjusted change in HbA1c from baseline in subjects with stage 3a CKD (eGFR 45 to 59 mL/min/1.73 m2) at week 24. |
| Change From Baseline in HbA1c in Subjects With Stage 3b CKD (eGFR 30 to 44 mL/Min/1.73 m2) at Week 24 | 24 weeks | A secondary objective is to evaluate the effect of bexagliflozin 20 mg on the placebo-adjusted change in HbA1c from baseline in subjects with stage 3b CKD (eGFR 30 to 44 mL/min/1.73 m2) at week 24. |
Countries
France, Japan, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bexagliflozin 20 mg Each subject will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. | 157 |
| Placebo Each subject will receive a placebo (inactive) tablet once daily for the duration of the study. | 155 |
| Total | 312 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Total | Placebo | Bexagliflozin 20 mg |
|---|---|---|---|
| Age, Continuous | 69.6 years STANDARD_DEVIATION 8.32 | 69.9 years STANDARD_DEVIATION 8.29 | 69.3 years STANDARD_DEVIATION 8.36 |
| BMI | 30.20 kg/m^2 STANDARD_DEVIATION 5.874 | 30.10 kg/m^2 STANDARD_DEVIATION 5.774 | 30.29 kg/m^2 STANDARD_DEVIATION 5.988 |
| Body Weight | 82.75 kg STANDARD_DEVIATION 20.82 | 82.59 kg STANDARD_DEVIATION 21.196 | 82.90 kg STANDARD_DEVIATION 20.509 |
| eGFR in Sub-group Stage 3a CKD: eGFR High Group | 51.52 mL/min/1.73 m^2 STANDARD_DEVIATION 4.884 | 51.27 mL/min/1.73 m^2 STANDARD_DEVIATION 4.404 | 51.76 mL/min/1.73 m^2 STANDARD_DEVIATION 5.307 |
| eGFR in Sub-group Stage 3b CKD: eGFR Low Group | 37.83 mL/min/1.73 m^2 STANDARD_DEVIATION 4.586 | 37.87 mL/min/1.73 m^2 STANDARD_DEVIATION 4.629 | 37.79 mL/min/1.73 m^2 STANDARD_DEVIATION 4.572 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 17 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 287 Participants | 138 Participants | 149 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Height | 164.8 cm STANDARD_DEVIATION 10.25 | 164.7 cm STANDARD_DEVIATION 10.58 | 164.8 cm STANDARD_DEVIATION 9.94 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 120 Participants | 59 Participants | 61 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 6 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 | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 171 Participants | 88 Participants | 83 Participants |
| Region of Enrollment France | 28 participants | 16 participants | 12 participants |
| Region of Enrollment Japan | 116 participants | 58 participants | 58 participants |
| Region of Enrollment Spain | 65 participants | 31 participants | 34 participants |
| Region of Enrollment United States | 103 participants | 50 participants | 53 participants |
| SBP Categories < 130 mm Hg | 92 Participants | 42 Participants | 50 Participants |
| SBP Categories > 130 mm Hg | 220 Participants | 113 Participants | 107 Participants |
| Sex: Female, Male Female | 116 Participants | 51 Participants | 65 Participants |
| Sex: Female, Male Male | 196 Participants | 104 Participants | 92 Participants |
| Subjects in eGFR Sub-group at Baseline Stage 3a CKD: eGFR High Group | 166 Participants | 80 Participants | 86 Participants |
| Subjects in eGFR Sub-group at Baseline Stage 3b CKD: eGFR Low Group | 146 Participants | 75 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 157 | 0 / 155 |
| other Total, other adverse events | 56 / 157 | 42 / 155 |
| serious Total, serious adverse events | 11 / 157 | 9 / 155 |
Outcome results
Primary
Change From Baseline in HbA1c at 24 Weeks
The primary efficacy objective of this trial is to evaluate the placebo-adjusted change in HbA1c from baseline after 24 weeks of treatment with 20 mg bexagliflozin tablets in type 2 diabetic subjects with moderate renal impairment.
Time frame: 24 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin 20 mg | Change From Baseline in HbA1c at 24 Weeks | -0.59 percentage of glycated hemoglobin | Standard Error 0.065 |
| Placebo | Change From Baseline in HbA1c at 24 Weeks | -0.31 percentage of glycated hemoglobin | Standard Error 0.066 |
Comparison: This is a mixed-effects repeated measures analysis including region, screening anti-diabetic treatment regimen, baseline eGFR, treatment, visit, treatment-by-visit interaction and baseline HbA1c as a fixed effect covariate. Data from Weeks 6, 12, and 24 are used in the model.p-value: 0.002695% CI: [-0.46, -0.1]Mixed-effects repeated measures
Secondary
Change From Baseline in HbA1c in Subjects With Stage 3a CKD (eGFR 45 to 59 mL/Min/1.73 m2) at Week 24
A secondary objective is to evaluate the effect of bexagliflozin 20 mg on the placebo-adjusted change in HbA1c from baseline in subjects with stage 3a CKD (eGFR 45 to 59 mL/min/1.73 m2) at week 24.
Time frame: 24 weeks
Population: Subjects who had the eGFR between 45 and 59 mL/min/1.73 m2 are included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin 20 mg | Change From Baseline in HbA1c in Subjects With Stage 3a CKD (eGFR 45 to 59 mL/Min/1.73 m2) at Week 24 | -0.63 percentage of glycated hemoglobin | Standard Error 0.086 |
| Placebo | Change From Baseline in HbA1c in Subjects With Stage 3a CKD (eGFR 45 to 59 mL/Min/1.73 m2) at Week 24 | -0.44 percentage of glycated hemoglobin | Standard Error 0.089 |
p-value: 0.115695% CI: [-0.44, 0.05]Mixed-effects repeated measures
Secondary
Change From Baseline in HbA1c in Subjects With Stage 3b CKD (eGFR 30 to 44 mL/Min/1.73 m2) at Week 24
A secondary objective is to evaluate the effect of bexagliflozin 20 mg on the placebo-adjusted change in HbA1c from baseline in subjects with stage 3b CKD (eGFR 30 to 44 mL/min/1.73 m2) at week 24.
Time frame: 24 weeks
Population: Subjects with eGFR between 30 and 44 mL/min/1.73 m2 were included in this anlaysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin 20 mg | Change From Baseline in HbA1c in Subjects With Stage 3b CKD (eGFR 30 to 44 mL/Min/1.73 m2) at Week 24 | -0.57 percentage of glycated hemoglobin | Standard Error 0.1 |
| Placebo | Change From Baseline in HbA1c in Subjects With Stage 3b CKD (eGFR 30 to 44 mL/Min/1.73 m2) at Week 24 | -0.20 percentage of glycated hemoglobin | Standard Error 0.097 |
p-value: 0.007895% CI: [-0.65, -0.1]Mixed-effects repeated measures
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) in Subjects With Baseline SBP ≥ 130 mm Hg at Week 24
A secondary objective is to evaluate the effect of bexagliflozin 20 mg on the placebo-adjusted change from baseline in SBP to in subjects with baseline SBP ≥ 130 mm Hg at Week 24.
Time frame: 24 weeks
Population: Only number of subjects with a value at baseline and at Week 24 is included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin 20 mg | Change From Baseline in Systolic Blood Pressure (SBP) in Subjects With Baseline SBP ≥ 130 mm Hg at Week 24 | -10.14 mm Hg | Standard Error 1.477 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) in Subjects With Baseline SBP ≥ 130 mm Hg at Week 24 | -7.51 mm Hg | Standard Error 1.46 |
p-value: 0.203595% CI: [-6.7, 1.44]Mixed-effects repeated measures
Secondary
Change in Body Weight From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2
A secondary objective is to evaluate the effect of bexagliflozin 20 mg on the placebo-adjusted change in BMI from baseline to week 24 in subjects with a BMI ≥ 25 kg/m2.
Time frame: 24 weeks
Population: Only number of subjects with a value at baseline and at the specific visit is included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bexagliflozin 20 mg | Change in Body Weight From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2 | -2.31 kg | Standard Error 0.265 |
| Placebo | Change in Body Weight From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2 | -0.55 kg | Standard Error 0.269 |
p-value: <0.000195% CI: [-2.5, -1.03]Mixed-effects repeated measures