An Integrated Assessment of the Safety and Effectiveness of Bexagliflozin for the Management of Essential Hypertension

Study Overview
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Brief Summary
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This integrated assessment consists of two studies, 603A and 603B, to be carried out sequentially in a common study population. Participating subjects informed of the trial design and their consent to participate in both studies were to be obtained in a single consent form. Approximately 680 male or female adult subjects were to be enrolled.

Detailed Description
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THR-1442-C-603 is an integrated assessment of the potential utility of bexagliflozin tablets, 20 mg for the treatment of essential hypertension. It is composed of two studies, 603A and 603B, measuring effects in a common population. 603A was a multicenter double-blind parallel group placebo-controlled study conducted to determine the placebo-adjusted change from baseline to week 12 in the mean ambulatory systolic blood pressure (SBP) of approximately 680 subjects considered generally representative of the adult hypertensive population in the United States. Secondary endpoints included the placebo-adjusted change from baseline to week 12 of the mean office seated systolic blood pressure, the change to week 12 of the mean ambulatory and mean office seated diastolic blood pressure, the proportion of subjects achieving prespecified goals for absolute systolic and diastolic blood pressure as well as prespecified goals for reduction in systolic and diastolic blood pressure, measured by ambulatory and seated office measurement methodology. A603B was a multicenter double-blind parallel group placebo-controlled randomized withdrawal study conducted to determine the durability of the antihypertensive effect of bexagliflozin tablets, 20 mg, in a population not pre-selected for existing diabetes. All subjects entered a 12 week run-in period during which they self-administered open label bexagliflozin tablets, 20 mg once daily. At week 12 a baseline ambulatory blood pressure monitoring (ABPM) measurement was made, and the subjects were randomized one to one to receive either bexagliflozin tablets, 20 mg or bexagliflozin tablets, placebo. After a 12 week treatment period a second ABPM measurement was made. The primary endpoint was the intergroup difference in the change from baseline in the mean SBP.

Official Title
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An Integrated Assessment of the Safety and Effectiveness of Bexagliflozin Tablets, 20 mg, for the Management of Essential Hypertension

Conditions
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Essential Hypertension

Intervention / Treatment
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* Drug: Bexagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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To be eligible for randomization a prospective subject was to be: Male or female of age ≥ 20 years Diagnosed with essential hypertension and exhibiting an office seated SBP ≥ 140 and < 180 mm Hg Unmedicated or prescribed no more than 4 agents for hypertension. Unmedicated subjects were subjects who had never taken medications for hypertension or had not taken any anti-hypertensive medication for at least 3 months. A stable dose meant no change in dose or frequency had taken place in the 4 weeks prior to the screening visit If female and of childbearing potential, willing to use an adequate method of contraception and to not become pregnant for the duration of the study. Willing and able to return for all clinic visits and to complete all study-required procedures Able to self-medicate during the run-in period, omitting no more than one day of dosing Shown to have a seated SBP ≥ 140 and < 180 mm Hg Shown to exhibit a mean 24 h SBP ≥ 135 mm Hg Prospective participants exhibiting any of the following characteristics were to be excluded from the study: Diagnosis of type 1 diabetes mellitus or maturity-onset/diabetes of the young (MODY) Known history of secondary or malignant hypertension Seated diastolic blood pressure (DBP) >110 mm Hg at screening Taking insulin for diabetes Prescribed more than 4 anti-hypertension medications Having a genitourinary tract infection within 6 weeks of screening or history of ≥ 3 genitourinary infections requiring treatment within the last 6 months Having cancer, active or in remission for < 3 years History of alcohol or illicit drug abuse in the past 2 years History of myocardial infarction, stroke or hospitalization for heart failure in the prior 6 months Previous exposure to bexagliflozin or EGT0001474 History of hypertensive emergency History of sodium glucose linked transporter 2 (SGLT2) inhibitor treatment in the last 3 months Known intolerance or allergy to SGTL2 inhibitors 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 Pregnancy or nursing Current participation in another interventional trial or having been exposed to an investigational drug within 30 days or 7 half-lives of screening, whichever is longer Arm circumference too large or small to allow accurate ambulatory monitoring History of kidney transplant Occupational or other lifestyle factors that could hamper the collection of valid ABPM data 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 Estimated glomerular filtration rate (eGFR), as calculated by the modification of diet in renal disease study equation (MDRD), < 45 mL/min/1.73 m2 or requiring dialysis HbA1c > 9.5% Positive urine pregnancy test for female subjects of child bearing potential 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 eGFR, as calculated by the modification of diet in renal disease study equation (MDRD), < 45 mL/min/1.73 m2 or requiring dialysis HbA1c > 9.5% Positive urine pregnancy test for female subjects of child bearing potential

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The primary endpoint of study 603A is the change from baseline (Day 1) to week 12 in the 24-hour average SBP of the bexagliflozin group compared to the placebo group using a superiority testing at an overall two-sided 0.05 level of significance. The primary endpoint of study 603B is the change from week 12 (cumulative week 24) to week 24 (cumulative week 36) in the 24-hour average SBP in the bexagliflozin group compared to the placebo group using a superiority testing at an overall two-sided 0.05 level of significance.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Sequence 1<br>Period 1: Placebo Period 2: Bexagliflozin Period 3: Bexagliflozin | Drug: Bexagliflozin<br>* Bexagliflozin tablet, 20 mg<br>* Other names: EGT0001442;Drug: Placebo<br>* Placebo (inactive) tablet to match the active drug<br>|
| Other: Sequence 2<br>Period 1: Placebo Period 2: Bexagliflozin Period 3: Placebo | Drug: Bexagliflozin<br>* Bexagliflozin tablet, 20 mg<br>* Other names: EGT0001442;Drug: Placebo<br>* Placebo (inactive) tablet to match the active drug<br>|
| Other: Sequence 3<br>Period 1: Bexagliflozin Period 2: Bexagliflozin Period 3: Bexagliflozin | Drug: Bexagliflozin<br>* Bexagliflozin tablet, 20 mg<br>* Other names: EGT0001442;|
| Other: Sequence 4<br>Period 1: Bexagliflozin Period 2: Bexagliflozin Period 3: Placebo | Drug: Bexagliflozin<br>* Bexagliflozin tablet, 20 mg<br>* Other names: EGT0001442;Drug: Placebo<br>* Placebo (inactive) tablet to match the active drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of the 24 Hour Mean Systolic Blood Pressure From Baseline (Day 1) to Week 12 | Change of the 24 hour mean systolic blood pressure in the bexagliflozin group compared to placebo | Baseline (Day 1) to week 12 | 
| Change of the 24 Hour Mean Systolic Blood Pressure From Cumulative Week 24 to Week 36 | Change of the 24 hour mean systolic blood pressure in the bexagliflozin group compared placebo | Change from week 24 to week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 603A, Reduction of Mean Ambulatory Systolic Blood Pressure | Proportion of subjects who achieve a reduction of mean ambulatory systolic blood pressure of 10 mm Hg or greater | Baseline (Day 1) to week 12 | 
| 603A, Mean Ambulatory Systolic Blood Pressure of 135 mm Hg or Less | Proportion of subjects who achieve a mean ambulatory systolic blood pressure of 135 mm Hg or less | Baseline (Day 1) to week 12 | 
| 603A, Change in Seated Office Systolic Blood Pressure | Placebo-adjusted change in seated office systolic blood pressure | Baseline (Day 1) to week 12 | 
| 603A, Seated Office Systolic Blood Pressure of 140 mm Hg or Less | Proportion of subjects who achieve a seated office systolic blood pressure of 140 mm Hg or less | Baseline (Day 1) to week 12 | 
| 603A, Change in Mean Ambulatory Diastolic Blood Pressure | Placebo-adjusted change in mean ambulatory diastolic blood pressure | Baseline (Day 1) to week 12 | 
| 603A, Mean Ambulatory Diastolic Blood Pressure of 87 mm Hg or Less | Proportion of subjects who achieve a mean ambulatory diastolic blood pressure of 87 mm Hg or less | Baseline (Day 1) to week 12 | 
| 603A, Reduction of Mean Ambulatory Diastolic Blood Pressure of 4 mm Hg or Greater | Proportion of subjects who achieve a reduction of mean ambulatory diastolic blood pressure of 4 mm Hg or greater | Baseline (Day 1) to week 12 | 
| 603A, Change in Seated Office Diastolic Blood Pressure | Placebo-adjusted change in seated office diastolic blood pressure | Baseline (Day 1) to week 12 | 
| 603A, Seated Office Diastolic Blood Pressure of 90 mm Hg or Less | Proportion of subjects who achieve a mean seated office diastolic blood pressure of 90 mm Hg or less | Baseline (Day 1) to week 12 | 
| 603B, Change in Seated Office Systolic Blood Pressure | Placebo-adjusted change from week 12 to week 24 in seated office systolic blood pressure | Week 12 (cumulative week 24) to Week 24 (cumulative week 36) | 
| 603B, Change in Mean Ambulatory Diastolic Blood Pressure | Placebo-adjusted change in mean ambulatory diastolic blood pressure | Week 12 (cumulative week 24) to Week 24 (cumulative week 36) | 
| 603B, Change in Seated Office Diastolic Blood Pressure | Placebo-adjusted change from week 12 to week 24 in seated office diastolic blood pressure | Week 12 (cumulative week 24) to Week 24 (cumulative week 36) |