An Efficacy and Safety Study of Azilsartan Medoxomil Compared to Valsartan and Olmesartan in Participants With Essential Hypertension.

Official Title: “A Double-Blind, Randomized, Placebo-Controlled, 5-Arm Titration Study to Evaluate the Efficacy and Safety of TAK-491 When Compared With Valsartan and Olmesartan in Subjects With Essential Hypertension”

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

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 successfully maintain control.

A major component of blood pressure regulation is the renin-angiotensin-aldosterone system.

This is a system of hormone-mediated feedback interactions that result in the relaxation or constriction of blood vessels in response to various stimuli. Angiotensin II, a polypeptide hormone, is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme as part of the renin-angiotensin-aldosterone system. Angiotensin II is the principal pressor agent of the renin-angiotensin-aldosterone system and has multiple effects on the cardiovascular system and on electrolyte homeostasis.

TAK-491 (azilsartan medoxomil) is an angiotensin II type 1 receptor antagonist currently being tested as a treatment for essential hypertension.

Study participation is anticipated to be about 10 weeks. Multiple procedures will occur at each visit which may include fasting, blood collection, urine collection, physical examinations, electrocardiograms and ambulatory blood pressure monitoring. Outside of the study center, participants will be required wear an ambulatory blood pressure monitoring device at 24 hour intervals.

Intervention(s) in this Clinical Trial

• Drug: Azilsartan medoxomil
  • Azilsartan medoxomil 20 mg, tablets and matching placebo comparator orally once daily for two weeks. Increased to azilsartan medoxomil 40 mg tablets and matching placebo comparator orally, once daily for up to four weeks.
• Drug: Azilsartan medoxomil
  • Azilsartan medoxomil 40 mg, tablets and matching placebo comparator orally, once daily for two weeks. Increased to Azilsartan medoxomil 80 mg, tablets and matching placebo comparator orally, once daily for up to four weeks.
• Drug: Valsartan
  • Valsartan 160 mg, tablets, and matching placebo comparator orally, once daily for two weeks. Increased to Valsartan 320 mg, tablets, and matching placebo comparator, orally, once daily for up to four weeks.
• Drug: Olmesartan
  • Olmesartan 20 mg, tablets and matching placebo comparator, orally, once daily for two weeks. Increased to Olmesartan 40 mg, tablets and matching placebo comparator, orally, once daily for up to four weeks.
• Drug: Placebo
  • Matching placebo, orally, once daily for up to six weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Azilsartan Medoxomil 40 mg QD
• Experimental: Azilsartan Medoxomil 80 mg QD
• Active Comparator: Valsartan 320 mg QD
• Active Comparator: Olmesartan 40 mg QD
• Placebo Comparator: Placebo QD

Primary Measures

• Change From Baseline in the 24-hour Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No

Secondary Measures

• Change From Baseline in Mean Trough Clinic Sitting Systolic Blood Pressure.
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Change From Baseline in the 24-hour Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Change From Baseline in Mean Trough Clinic Sitting Diastolic Blood Pressure
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Change From Baseline in Daytime (6am to 10 pm) Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Change From Baseline in Daytime (6am to 10 pm) Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Change From Baseline in the Nighttime (12 am to 6 am) Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Change From Baseline in the Nighttime (12 am to 6 am) Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Change From Baseline in the 12-hour Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Change From Baseline in the 12-hour Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Change From Baseline in the Trough (22-24-hr) Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Change From Baseline in the Trough (22-24-hr) Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Percentage of Participants Who Achieve a Clinic Systolic Blood Pressure Response, Defined as < 140 mm Hg and/or Reduction From Baseline ≥ 20 mm Hg
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Percentage of Participants Who Achieve a Clinic Diastolic Blood Pressure Response, Defined as < 90 mm Hg and/or Reduction From Baseline ≥ 10 mm Hg
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No
• Percentage of Participants Who Achieve Both a Clinic Diastolic and Systolic Blood Pressure Response
  • Time Frame: Baseline and Week 6.
    Safety Issue?: No

Inclusion Criteria:

• 1. Essential hypertension (sitting systolic blood pressure between 150 and 180 mm Hg, inclusive, at Day -1 and 24-hour mean systolic blood pressure between 130 and 170 mm
• Hg, inclusive, at Day 1).
• 2. Capable of understanding and complying with protocol requirements.
• 3. 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
• 4. Clinical laboratory evaluations within the reference range for the testing laboratory or the results are deemed not clinically significant for inclusion into this study by the investigator.
• 5. Willing to discontinue current antihypertensive medications at Screening Day 21 visit. If the participant is on amlodipine prior to Screening, the participant is willing to discontinue this medication at Screening Day -28.

Exclusion Criteria:

• 1. Sitting diastolic blood pressure greater than 114 mm Hg at Day -1 (day prior to Randomization).
• 2. Baseline 24-hour ambulatory blood pressure monitor reading of insufficient quality.
• 3. Taking or expected to take an excluded medication as described in the Excluded
• Medications.
• 4. Hypersensitive to angiotensin II receptor blockers.
• 5. History of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.
• 6. Clinically significant cardiac conduction defects.
• 7. Hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
• 8. Secondary hypertension of any etiology.
• 9. Noncompliant (less than 70% or greater than 130%) with study medication during run-in period.
• 10. Moderate to severe renal dysfunction or disease.
• 11. Known or suspected unilateral or bilateral renal artery stenosis.
• 12. History of drug or alcohol abuse within the past 2 years.
• 13. Previous 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 participants with basal cell or stage I squamous cell carcinoma of the skin).
• 14. Type 1 or poorly-controlled type 2 diabetes mellitus (glycosylate hemoglobin greater than 8.0%) at Screening.
• 15. Hyperkalemia as defined by the central laboratory normal reference range at
• Screening.
• 16. Alanine aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice at Screening.
• 17. Upper arm circumference less than 24 cm or greater than 42 cm.
• 18. Works night (3rd) shift (defined as 11 PM [2300] to 7 AM [0700]).
• 19. Unwilling or unable to comply with the protocol or scheduled appointments.
• 20. Currently is participating in another investigational study or has participated in an investigational study within 30 days prior to Randomization.
• 21. Any other serious disease or condition at Screening or Randomization that would compromise participant's safety, might affect life expectancy, or make it difficult to successfully manage and follow the subject according to the protocol.
• 22. Has been randomized in a previous azilsartan medoxomil study.
• 23. Is required to take or continues taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Takeda Global Research & Development Center, Inc. Industry

Overall Clinical Trial Officials and Contacts

Executive Medical Director Clinical Science Study Director Takeda Global Research & Development Center, Inc.  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00696436

Study ID Number: 01-06-TL-491-019

ClinicalTrials.gov Identifier: NCT00696436

Health Authority: United States: Food and Drug Administration

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