| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
| E.1.2 | System Organ Class | 100000004861 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary efficacy objective of this trial is to evaluate the placebo-adjusted change in HbA1c from baseline after 24 weeks of exposure to bexagliflozin in type 2 diabetic subjects with increased risk of cardiovascular adverse events.
The primary safety objective of this study is the contribution of at least 134 major adverse cardiovascular events (MACE+) to an eventual meta-analysis that is intended to exclude a hazard ratio of 1.8 or greater for subjects exposed to bexagliflozin compared to subjects exposed to placebo. MACE+ is defined as cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, or hospitalization for unstable angina.
An additional objective is the evaluation of the safety of exposure to bexagliflozin for a minimum of 52 weeks in a treatment population that is at elevated risk for major adverse cardiovascular events. |
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| E.2.2 | Secondary objectives of the trial |
Efficacy objectives:
•To evaluate the effect of bexagliflozin compared to placebo on the change in HbA1c from baseline to week 24 in randomized subjects who have been prescribed insulin to control their diabetes•To evaluate the effect of bexagliflozin on the change in systolic blood pressure from baseline to week 24 in subjects with baseline systolic blood pressure ≥ 140 mmHg compared to placebo•To assess the effect of bexagliflozin treatment on the change in HbA1c versus placebo over time•To evaluate the effect of bexagliflozin treatment on the change in fasting plasma glucose (FPG) versus placebo over time
•To measure the proportion of subjects requiring an intensification of anti-diabetic regimen versus placebo over time
•To measure the proportion of subjects requiring a relaxation of their anti-diabetic regimen versus placebo over time
•To measure the incidence of hospitalization for heart failure among all subjects and among subjects with a history of heart failure at baseline |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Measurement of cardiovascular biomarkers at baseline and week 12 in an exploratory study to increase the understanding of bexagliflozin treatment effect on the biomarkers that are relevant in the CV disease diagnosis and prognosis. |
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| E.3 | Principal inclusion criteria |
The study population will include:
1. Male or female adult subjects with an age ≥40 years
2. Subjects with a diagnosis of T2DM
3. Subjects with HbA1c values of 7.0 – 11%, inclusive
4. Subjects with fasting plasma glucose (FPG) ≤ 300 mg/dL at screening
5. Subjects who have a regimen for treatment of T2DM that has been stable for the past 3 months. A stable regimen is defined as: no changes in dose or frequency of OHAs or GLP-1 agonists, or < 20% variability in total daily insulin dose.
6. Subjects who present with at least one of the following 3 histories:
Group 1: A history of atherosclerotic vascular disease as defined by one or more of the following:
a) myocardial infarction (MI) or ischemic (non-hemorrhagic) stroke
> 3 months but ≤ 5 years prior to screening or
b) documented history of coronary, carotid, or peripheral arterial revascularization (coronary artery bypass grafting must have occurred ≥ 5 years prior to screening)
Group 2: A history of NYHA class II or class III heart failure (Appendix 4) at the time of screening. A history of heart failure is defined as:
• documented left ventricular ejection fraction (LVEF) ≤ 40% and no subsequent LVEF > 40% within 6 months of screening, or
• (i) an NT-proBNP >300 pg/mL and no evidence of atrial fibrillation/flutter (AF) at the time of the screening ECG or an NT-proBNP >900 pg/mL and evidence of AF at the time of the screening ECG and (ii) either (a) structural heart disease documented by report of left atrial enlargement or left ventricular hypertrophy, or (b) exhibiting
symptom(s) of HF requiring treatment with diuretic(s) for at least 30 days prior to screening.
Group 3: Age ≥ 55 years with 2 or more of the following:
a) diabetes duration of ≥ 10 years,
b) uncontrolled hypertension defined as SBP > 140 mmHg despite 3 or more anti-hypertensive medications
c) current smoking,
d) urine albumin:creatinine ratio (UACR) > 30 mg/g,
e) eGFR of 45 to 60 mL/min/1.73 m2, or
f) HDL < 1 mmol/L (38 mg/dL)
7. Female subjects of childbearing potential who are willing to use an adequate method of contraception and to not become pregnant for the duration of the study. Adequate contraceptive measures include, but are not limited to, oral contraceptives, intrauterine devices, Depo-Provera, Norplant, hormonal contraceptive implants, bilateral tubal ligation, partner with vasectomy, condom or diaphragm plus contraceptive sponge, foam, or jelly, and abstinence
8. Subjects who are willing and able to return for all clinic visits and to complete all study required procedures, including self-monitored blood glucose (SMBG) measurement, and take run-in medication, missing no more than one dose due to non-compliance.
9. Subjects who receive anti-hypertensive medications at a stable dosage for ≥ 2 weeks prior to randomization
10. Subjects who receive lipid modifying therapy on a stable regimen for 6 weeks prior to randomization
11. Subjects who have seated SBP < 170 mmHg and DBP < 110 mmHg at screening. |
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| E.4 | Principal exclusion criteria |
Patients who exhibit any of the following characteristics will be excluded from the study.
1. Diagnosis of type 1 diabetes mellitus or maturity–onset/diabetes of the young (MODY)
2. Hemoglobinopathy that affects HbA1c measurement
3. Frequent symptomatic hypoglycemia (greater than one episode per week on average)
4. Genitourinary tract infection within 6 weeks of screening or history of ≥ 3 genitourinary infections requiring treatment within the last 6 months
5. Cancer, active or in remission for < 3 years (Non-melanoma skin cancer or basal cell carcinoma or carcinoma in situ of the cervix will not be grounds for exclusion)
6. 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 x upper limit of normal (ULN) with the exception of isolated Gilbert’s syndrome); or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x ULN
8. History of MI, stroke or hospitalization for heart failure in the prior 3 months
9. Evidence of NYHA class IV heart failure at screening or randomization
10. Presently scheduled for percutaneous coronary intervention, coronary artery bypass grafting or any surgical procedure
11. Previous treatment with bexagliflozin or EGT0001474
12. Currently or within 3 months of taking any SGLT2 inhibitors
13. 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
14. Prior renal transplantation or evidence of nephrotic syndrome, defined as a urine albumin: creatinine ratio (UACR) > 2000 mg/g, at screening
15. Implantation of a cardiac resynchronization therapy device within 3 months prior to screening or intent to implant a cardiac resynchronization therapy (CRT) within 6 months following screening
16. Diagnosis of peripartum or chemotherapy-induced cardiomyopathy within 12 months prior to screening
17. Symptomatic bradycardia or second or third degree atrioventricular block without a pacemaker
18. eGFR, as calculated by the modification of diet in renal disease study equation (MDRD), < 45 mL/min/1.73 m2 or requiring dialysis
19. Pregnant or nursing
20. Currently participating in another interventional trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy hypothesis is that bexagliflozin reduces HbA1c after 24 weeks of treatment when compared to placebo. The primary efficacy analysis on change in HbA1c at week 24 is based on the ITT using all observed data. Missing data will be handled using a
mixed model repeated measures (MMRM) approach and will include terms for visit, treatment, treatment-by-visit interaction and randomization stratification factors as fixed effects and the corresponding baseline HbA1c value as a fixed effect covariate. Least squares mean treatment differences between the bexagliflozin group and the placebo group will be estimated from the model at week 24 with the corresponding p-values and their two-sided 95% CIs presented. An unstructured covariance will be used to model the within-subject correlation. In the unlikely event the model with the unstructured covariance structure does not converge, an autoregressive(1) covariance structure will be used. HbA1c values obtained after the start of rescue medication will not be excluded from the analysis.
As a secondary sensitivity analysis, the multiple imputation method will be used to impute missing observations (including observations obtained after rescue medication) prior to carrying out the MMRM analysis. To further examine the sensitivity of the analysis, a last observation carried forward (LOCF) method will then be used to impute the missing observations prior to carrying out the MMRM model.
For supportive analyses, the primary efficacy endpoint will be analyzed with observed available data using the PP analysis sets in a similar manner as above. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The Primary endpoint will be determined at baseline and at 24 weeks with supportive additional data for the model provided at 6 and 12 weeks. |
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| E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoints include:
•Change in HbA1c from baseline to week 24 in randomized subjects who
have been prescribed insulin to control their diabetes
• Change in body weight from baseline to week 48 in subjects with a BMI ≥ 25 kg/m2
• Change in SBP from baseline to week 24 in subjects with baseline systolic blood pressure ≥ 140 mmHg
The exploratory secondary efficacy endpoints include:
• Change from baseline in HbA1c over time
• Change from baseline in FPG over time
• Change from baseline in body weight over time
• Change from baseline in SBP over time
• Requirement of additional anti-diabetic medications, including insulin; and time to first use of additional anti-diabetic medication
• Requirement of reduced anti-diabetic medications, including insulin dose over time
• Hospitalization for heart failure in all subjects and in subjects with a history of heart failure; and time to hospitalization for heart failure in subjects in all subjects and in subjects with a history of heart failure
• Time to hospitalization for heart failure in subjects in all subjects and
in subjects with a history of heart failure
The other safety endpoints include:
• Time to a 5-point composite adjudicated endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization
• Time-to a 6-point composite adjudicated endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure, and coronary revascularization; and time to onset of event
• Time to individual events including all-cause mortality, CV death, non-fatal MI, non-fatal stroke, transient ischemic attack, hospitalization for unstable angina, hospitalization for heart failure, and coronary revascularization; and time to onset of each event
• Incidence of treatment emergent AEs (TEAEs) of interest
• Incidence of amputations
• Change from baseline in eGFR by study visit
• Change from baseline in UACR by study visit
AEs of special interest include the following categories:
• Genital mycotic infections
• Urinary tract infections including urosepsis and pyelonephritis
• Diuretic effects including hypovolemia
• Hypotension episodes
• Hepatotoxicity
• Hypoglycemia
• Falls and fractures
• Malignancies
• Hypersensitivity reactions
• Acid-base disorders including DKA
• Renal failure events
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary efficacy endpoints:
Body weight: baseline and weeks 6, 12, 24, 36 and 48 ; SBP: baseline and weeks 6, 12 and 24.
Exploratory secondary efficacy endpoints:
HbA1C, FPG, body weight, SBP: baseline, weeks 6, 12, 24, 36, 48 and every 24 weeks thereafter (note study is event driven, so exact length of study duration is not known.)
Additional, first use or reduced use of anti-diabetic medications and hospitalization for heart failure : throughout study
The other safety endpoints:
All of the MACE+ events will be recorded during the study and analysed as noted above at study end
Incidence of TEAEs: throughout study
eGFR: baseline, week 12, 24, 36, 48 and then every 24 weeks thereafter
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Czech Republic |
| Denmark |
| Germany |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Russian Federation |
| Taiwan |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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