Clinical trial NCT03514641: An Integrated Assessment of the Safety and Effectiveness of Bexagliflozin for the Management of Essential Hypertension
Official title: An Integrated Assessment of the Safety and Effectiveness of Bexagliflozin Tablets, 20 mg, for the Management of Essential Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Essential Hypertension
Lead sponsor: Theracos
Sponsor class: INDUSTRY
First posted: 2018-05-02
Enrollment: 673
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change of the 24 Hour Mean Systolic Blood Pressure From Baseline (Day 1) to Week 12
timeFrame: Baseline (Day 1) to week 12
measure: Change of the 24 Hour Mean Systolic Blood Pressure From Cumulative Week 24 to Week 36
timeFrame: Change from week 24 to week 36
Secondary outcomes:
measure: 603A, Reduction of Mean Ambulatory Systolic Blood Pressure
timeFrame: Baseline (Day 1) to week 12
measure: 603A, Mean Ambulatory Systolic Blood Pressure of 135 mm Hg or Less
timeFrame: Baseline (Day 1) to week 12
measure: 603A, Change in Seated Office Systolic Blood Pressure
timeFrame: Baseline (Day 1) to week 12
measure: 603A, Seated Office Systolic Blood Pressure of 140 mm Hg or Less
timeFrame: Baseline (Day 1) to week 12
measure: 603A, Change in Mean Ambulatory Diastolic Blood Pressure
timeFrame: Baseline (Day 1) to week 12
measure: 603A, Mean Ambulatory Diastolic Blood Pressure of 87 mm Hg or Less
timeFrame: Baseline (Day 1) to week 12
measure: 603A, Reduction of Mean Ambulatory Diastolic Blood Pressure of 4 mm Hg or Greater
timeFrame: Baseline (Day 1) to week 12
measure: 603A, Change in Seated Office Diastolic Blood Pressure
timeFrame: Baseline (Day 1) to week 12
measure: 603A, Seated Office Diastolic Blood Pressure of 90 mm Hg or Less
timeFrame: Baseline (Day 1) to week 12
measure: 603B, Change in Seated Office Systolic Blood Pressure
timeFrame: Week 12 (cumulative week 24) to Week 24 (cumulative week 36)
measure: 603B, Change in Mean Ambulatory Diastolic Blood Pressure
timeFrame: Week 12 (cumulative week 24) to Week 24 (cumulative week 36)
measure: 603B, Change in Seated Office Diastolic Blood Pressure
timeFrame: Week 12 (cumulative week 24) to Week 24 (cumulative week 36)
Other outcomes:
measure: Integrated 603A and 603B, Effects on Mean Ambulatory Systolic and Diastolic Blood Pressure
timeFrame: Baseline (Day 1) to cumulative week 36
measure: Integrated 603A and 603B, Effects on Seated Office Systolic and Diastolic Blood Pressure
timeFrame: Baseline (Day 1) to cumulative week 36
Locations:
city: Birmingham
country: United States
facility: Clinical Research Site
state: Alabama
city: Birmingham
country: United States
facility: Clinical Research Site
state: Alabama
city: Birmingham
country: United States
facility: Clinical Research Site
state: Alabama
city: Foley
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facility: Clinical Research Site
state: Alabama
city: Gulf Shores
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facility: Clinical Research Site
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city: Glendale
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state: Arizona
city: Mesa
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city: Phoenix
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facility: Clinical Research Site
state: Arizona
city: Tucson
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city: Anaheim
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state: California
city: Bellflower
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city: Fair Oaks
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facility: Clinical Research Site
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city: Fresno
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facility: Clinical Research Site
state: California
city: Lincoln
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city: Los Angeles
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city: San Gabriel
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city: Santa Rosa
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state: California
city: Upland
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city: Colorado Springs
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city: Denver
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city: Golden
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state: Connecticut
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state: Georgia
city: Decatur
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city: Lithonia
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city: Chicago
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city: Chicago
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facility: Clinical Research Site
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city: Avon
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city: Evansville
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city: Indianapolis
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city: Paducah
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city: Versailles
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city: New Orleans
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state: Louisiana
city: Auburn
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facility: Clinical Research Site
state: Maine
city: Silver Spring
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city: Edina
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state: Minnesota
city: Bridgeton
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city: Henderson
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state: Nevada
city: Las Vegas
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city: Trenton
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state: New Jersey
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state: New Mexico
city: Bronx
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facility: Clinical Research Site
state: New York
city: Brooklyn
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state: New York
city: Hartsdale
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state: New York
city: Shelby
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state: North Carolina
city: Akron
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state: Ohio
city: Cincinnati
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state: Ohio
city: Cincinnati
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state: Ohio
city: Columbus
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state: Ohio
city: Dayton
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city: Dublin
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state: Ohio
city: Grove City
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facility: Clinical Research Site
state: Ohio
city: Lyndhurst
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facility: Clinical Research Site
state: Ohio
city: Edmond
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state: Oklahoma
city: Oklahoma City
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state: Oklahoma
city: Portland
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facility: Clinical Research Site
state: Oregon
city: Altoona
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state: Pennsylvania
city: Hatboro
country: United States
facility: Clinical Research Site
state: Pennsylvania
city: Lincoln
country: United States
facility: Clinical Research Site
state: Rhode Island
city: Anderson
country: United States
facility: Clinical Research Site 2
state: South Carolina
city: Anderson
country: United States
facility: Clinical Research Site
state: South Carolina
city: Greer
country: United States
facility: Clinical Research Site
state: South Carolina
city: Kingsport
country: United States
facility: Clinical Research Site
state: Tennessee
city: Knoxville
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facility: Clinical Research Site
state: Tennessee
city: Arlington
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facility: Clinical Research Site
state: Texas
city: Dallas
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facility: Clinical Research Site
state: Texas
city: Houston
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state: Texas
city: Kingwood
country: United States
facility: Clinical Research Site
state: Texas
city: Mesquite
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facility: Clinical Research Site
state: Texas
city: Plano
country: United States
facility: Clinical Research Site
state: Texas
city: San Antonio
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state: Texas
city: Tomball
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facility: Clinical Research Site
state: Texas
city: Layton
country: United States
facility: Clinical Research Site
state: Utah
city: Murray
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state: Utah
city: West Jordan
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facility: Clinical Research Site
state: Utah
city: Arlington
country: United States
facility: Clinical Research Site
state: Virginia
city: Burke
country: United States
facility: Clinical Research Site
state: Virginia
city: Charlottesville
country: United States
facility: Clinical Research Site
state: Virginia
city: Danville
country: United States
facility: Clinical Research Site
state: Virginia
city: Manassas
country: United States
facility: Clinical Research Site
state: Virginia
city: Tacoma
country: United States
facility: Clinical Research Site
state: Washington
Study officials:
affiliation: Massachusetts General Hospital
name: Andrew Allegretti, M.D.
role: STUDY_DIRECTOR
References: