Efficacy and Safety of Azilsartan Medoxomil in Participants With Essential Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of azilsartan medoxomil, once daily (QD), compared to placebo and olmesartan in participants with essential hypertension.

Detailed Description
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Hypertension affects approximately 50 million individuals in the United States. As the population ages, the prevalence of hypertension will continue to increase if broad and effective preventive measures are not implemented. According to the World Health Organization, hypertension is the most common attributable cause of preventable death in developed nations, as uncontrolled hypertension greatly increases the risk of cardiovascular disease, cerebrovascular disease, and renal failure. Despite the availability of antihypertensive treatments, hypertension remains inadequately controlled; only about one-third of patients continue to maintain control successfully. TAK-491 (azilsartan medoxomil) is an angiotensin II receptor blocker and this study is being conducted to evaluate the efficacy and safety of oral azilsartan medoxomil compared to placebo and olmesartan in subjects with essential hypertension. Individuals who want to participate in this study will be required to provide written informed consent. Study participation is anticipated to be about 11 weeks. Multiple procedures will occur at each visit which may include fasting, blood collection, urine collection, vital signs including sitting blood pressure and pulse, body height and weight, physical examinations and electrocardiograms. Outside of the study center, participants will be required to wear an ambulatory blood pressure monitoring device at 24 hour intervals.

Official Title
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A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of TAK-491 in Subjects With Essential Hypertension

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Azilsartan medoxomil and olmesartan
* Drug: Azilsartan medoxomil and olmesartan
* Drug: Azilsartan medoxomil and olmesartan
* Drug: Olmesartan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Has essential hypertension (defined as sitting trough clinic systolic blood pressure between 150 and 180 mm Hg, inclusive at Day minus 1) and 24-hour mean systolic blood pressure greater than or equal to 130 mm Hg and less than or equal to 170 mm Hg at Day 1). Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study. Clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory or the results are deemed not clinically significant for inclusion into this study by the investigator. The subject is willing to discontinue current antihypertensive medications at the Screening Day minus 21 visit. If the subject is on amlodipine prior to screening, the subject is willing to discontinue this medication at Screening Day minus 28. Exclusion Criteria Sitting trough clinic diastolic blood pressure greater than 114 mm Hg at Day minus 1. Baseline 24-hour ambulatory blood pressure monitor reading of insufficient quality. History of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack. Clinically significant cardiac conduction defects (eg, third degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation or atrial flutter). Hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease. Secondary hypertension of any etiology. Is noncompliant (less than 70% or greater than 130%) with study medication during Placebo Run-In Period. Severe renal dysfunction or disease (based on calculated creatinine clearance less than 30 mL/min/1.73 m2) at Screening. Known or suspected unilateral or bilateral renal artery stenosis. History of drug abuse (defined as illicit drug use) or a history of alcohol abuse (defined as regular or daily consumption of more than 2 alcoholic drinks per day) within the past 2 years. History of cancer that has not been in remission for at least 5 years prior to the first dose of study drug. (This criterion does not apply to those subjects with basal cell or stage I squamous cell carcinoma of the skin). Type 1 or poorly controlled type 2 diabetes mellitus (glycosylated hemoglobin greater than 8.0%) at Screening. Alanine aminotransferase level greater than 2.5 times the upper limit of normal, active liver disease, or jaundice at Screening. Hyperkalemia (defined as serum potassium greater than the upper limit of normal per the central laboratory) at Screening. Upper arm circumference less than 24 cm or greater than 42 cm. Works night (3rd) shift (defined as 11 PM to 7 AM). Currently participating in another investigational study or has participated in an investigational study within 30 days prior to Screening. Any other serious disease or condition at Screening (or Randomization) that would compromise subject safety, might affect life expectancy, or make it difficult to successfully manage and follow the subject according to the protocol. Randomized in a previous azilsartan medoxomil study.

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azilsartan Medoxomil 20 mg QD<br> | Drug: Azilsartan medoxomil and olmesartan<br>* Azilsartan medoxomil 20 mg, tablets, azilsartan medoxomil 40 mg placebo-matching tablets, azilsartan medoxomil 80 mg placebo-matching tablets and olmesartan 40 mg placebo-matching tablets, orally, for up to 6 weeks.<br>* Other names: Edarbi;|
| Experimental: Azilsartan Medoxomil 40 mg QD<br> | Drug: Azilsartan medoxomil and olmesartan<br>* Azilsartan medoxomil 40 mg, tablets, azilsartan medoxomil 20 mg placebo-matching tablets, azilsartan medoxomil 80 mg placebo-matching tablets and olmesartan 40 mg placebo-matching tablets, orally, for up to 6 weeks.<br>* Other names: Edarbi;|
| Experimental: Azilsartan Medoxomil 80 mg QD<br> | Drug: Azilsartan medoxomil and olmesartan<br>* Azilsartan medoxomil 80 mg, tablets, azilsartan medoxomil 20 mg placebo-matching tablets, azilsartan medoxomil 40 mg placebo-matching tablets and olmesartan 40 mg placebo-matching tablets, orally, once daily for up to 6 weeks.<br>* Other names: Edarbi;|
| Active Comparator: Olmesartan 40 mg QD<br> | Drug: Olmesartan<br>* Olmesartan 40 mg, tablets, azilsartan medoxomil 20 mg placebo-matching tablets, azilsartan medoxomil 40 mg placebo-matching tablets and azilsartan medoxomil 80 mg placebo-matching tablets, orally, once daily for up to 6 weeks.<br>* Other names: Benicar®;|
| Placebo Comparator: Placebo QD<br> | Drug: Placebo<br>* Azilsartan medoxomil 20 mg placebo-matching tablets, azilsartan medoxomil 40 mg placebo-matching tablets, azilsartan medoxomil 80 mg placebo-matching tablets, and olmesartan 40 mg placebo- matching tablets, orally, once daily for up to 6 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the 24-hour Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring. | The change in 24-hour mean systolic blood pressure measured at week 6 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 24-hour mean is the average of all measurements recorded for 24 hours after dosing. | Baseline and Week 6. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Trough Clinic Sitting Systolic Blood Pressure | The change in mean trough clinic sitting systolic blood pressure measured at final visit or week 6 relative to baseline. | Baseline and Week 6. | 
| Change From Baseline in the 24-hour Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring. | The change in 24-hour mean diastolic blood pressure measured at week 6 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 24-hour mean is the average of all measurements recorded for 24 hours after dosing. | Baseline and Week 6. | 
| Change From Baseline in Mean Trough Clinic Sitting Diastolic Blood Pressure | The change in mean trough clinic sitting diastolic blood pressure measured at final visit or week 6 relative to baseline. | Baseline and Week 6. | 
| Change From Baseline in Daytime (6am to 10 pm) Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring. | The change in daytime (6am to 10pm) mean systolic blood pressure measured at week 6 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Daytime mean is the average of all measurements recorded between the hours of 6 am and 10 pm. | Baseline and Week 6. | 
| Change From Baseline in Daytime (6am to 10 pm) Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring. | The change in daytime (6am to 10pm) mean diastolic blood pressure measured at week 6 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Daytime mean is the average of all measurements recorded between the hours of 6 am and 10 pm. | Baseline and Week 6. | 
| Change From Baseline in the Nighttime (12 am to 6 am) Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring. | The change in nighttime (12am to 6am) mean systolic blood pressure measured at week 6 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Nighttime mean is the average of all measurements recorded between the hours of 12 am and 6 am. | Baseline and Week 6. | 
| Change From Baseline in the Nighttime (12 am to 6 am) Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring. | The change in nighttime (12am to 6am) mean diastolic blood pressure measured at week 6 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Nighttime mean is the average of all measurements recorded between the hours of 12 am and 6 am. | Baseline and Week 6. | 
| Change From Baseline in the 12-hour Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring | The change in the 12-hour mean systolic blood pressure measured at week 6 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 12-hour mean is the average of all measurements recorded in the first 12 hours after dosing. | Baseline and Week 6. | 
| Change From Baseline in the 12-hour Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring | The change in the 12-hour mean diastolic blood pressure measured at week 6 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 12-hour mean is the average of all measurements recorded in the first 12 hours after dosing. | Baseline and Week 6. | 
| Change From Baseline in the Trough (22-24-hr) Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring. | The change in trough mean systolic blood pressure measured at week 6 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The trough mean is the average of all measurements recorded from 22 to 24 hours after dosing. | Baseline and Week 6. | 
| Change From Baseline in the Trough (22-24-hr) Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring. | The change in trough mean diastolic blood pressure measured at week 6 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The trough mean is the average of all measurements recorded from 22 to 24 hours after dosing. | Baseline and Week 6. | 
| Percentage of Participants Who Achieve a Clinic Systolic Blood Pressure Response, Defined as < 140 mm Hg and/or Reduction From Baseline ≥ 20 mm Hg | Percentage of participants who achieve a clinic systolic blood pressure response measured at week 6, defined as less than 140 mm Hg and/or reduction from baseline of greater than or equal to 20 mm Hg. Systolic blood pressure is the arithmetic mean of the 3 trough sitting systolic blood pressure measurements. | Baseline and Week 6. | 
| Percentage of Participants Who Achieve a Clinic Diastolic Blood Pressure Response, Defined as < 90 mm Hg and/or Reduction From Baseline ≥ 10 mm Hg | Percentage of participants who achieve a clinic diastolic blood pressure response measured at week 6, defined as less than 90 mm Hg and/or reduction from baseline of greater than or equal to 10 mm Hg. Diastolic blood pressure is the arithmetic mean of the 3 trough sitting diastolic blood pressure measurements. | Baseline and Week 6. | 
| Percentage of Participants Who Achieve Both a Clinic Diastolic and Systolic Blood Pressure Response | Percentage of participants who achieve both a clinic diastolic and systolic blood pressure response measured at week 6, defined as less than 90 mm Hg and/or reduction from baseline of greater than or equal to 10 mm Hg AND less than 140 mm Hg and/or reduction from baseline of greater than or equal to 20 mm Hg. Diastolic and systolic blood pressure is based on the arithmetic mean of the 3 sitting blood pressure measurements. | Baseline and Week 6. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Essential Hypertension, Cardiovascular Disease, High Blood Pressure, Drug Therapy