Efficacy and Safety of Azilsartan Medoxomil Co-Administered With Chlorthalidone in Participants With Essential Hypertension

Official Title: “A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of TAK-491 When Co-administered With Chlorthalidone in Subjects With Essential Hypertension”

The purpose of this study is to evaluate the efficacy and safety of azilsartan medoxomil, once daily (QD), co-administered with chlorthalidone in treating individuals with essential hypertension, compared to treatment with chlorthalidone alone.

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 that was shown to be a orally active antihypertensive agent with a prolonged duration of activity and good safety tolerability in a recent clinical study. Chlorthalidone is a thiazide-like diuretic that reduces blood pressure by decreasing intravascular volume through urinary salt and water excretion. By combining this action with azilsartan medoxomil, a greater reduction in blood pressure is expected than with either agent alone. For subjects requiring combination therapy, azilsartan medoxomil plus chlorthalidone offers a novel combination that may provide a more potent and safe combination for blood pressure reduction.

This study is being conducted to determine whether administration of azilsartan medoxomil in combination with chlorthalidone to subjects with uncontrolled hypertension is more effective in reducing blood pressure than chlorthalidone alone. This study is also being conducted to evaluate the safety and tolerability of azilsartan medoxomil combined with chlorthalidone.

Individuals who want to participate in this study will be required to provide written informed consent. Study participation is anticipated to be about 10 Weeks. Multiple procedures will occur at each visit which may include fasting, blood collection, urine collection, vital signs including sitting and standing blood pressure and pulse, body height and weight, physical examinations, electrocardiogram. Outside of the study center, participants will be required to wear an ambulatory blood pressure monitoring device at 24 hour intervals.

Intervention(s) in this Clinical Trial

• Drug: Azilsartan medoxomil and chlorthalidone
  • Azilsartan medoxomil 40 mg, tablets, orally, once daily; azilsartan medoxomil 80 mg placebo-matching tablets, orally, once daily; and chlorthalidone 25 mg, tablets, orally, once daily for up to 6 weeks.
• Drug: Azilsartan medoxomil and chlorthalidone
  • Azilsartan medoxomil 80 mg, tablets, orally, once daily; azilsartan medoxomil 40 mg placebo-matching tablets, orally, once daily and chlorthalidone 25 mg, tablets, orally, once daily for up to 6 weeks.
• Drug: Chlorthalidone
  • Chlorthalidone 25 mg, tablets, orally, once daily; azilsartan medoxomil 80 mg placebo-matching tablets, orally, once daily and azilsartan medoxomil 40 mg placebo-matching tablets, orally, once daily for up to 6 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Azilsartan Medoxomil 40 mg QD and Chlorthalidone 25 mg QD
• Experimental: Azilsartan Medoxomil 80 mg QD and Chlorthalidone 25 mg QD
• Active Comparator: Chlorthalidone 25 mg 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. Has essential hypertension (defined as sitting trough clinic systolic blood pressure between 160 and 190 mm Hg inclusive at Day minus 1 and 24-hour mean systolic blood pressure greater than or equal to 140 mm Hg and ≤ 180 mm Hg at Day 1).
• 2. 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.
• 3. Has clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory or results that are deemed not clinically significant for inclusion into this study by the investigator.
• 4. 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

• 1. Has sitting trough clinic diastolic blood pressure greater than 119 mmHg at Day minus 1.
• 2. Has a baseline 24 hour ambulatory blood pressure monitor reading of insufficient quality.
• 3. 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.
• 4. Recent history (within the last 6 months) of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.
• 5. Clinically significant cardiac conduction defects (for example, 3rd degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation).
• 6. Hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
• 7. The subject has secondary hypertension of any etiology.
• 8. Non-compliant (less than 70% or greater than 130%) with study medication
• 9. during the placebo run- in period.
• 10. Severe renal dysfunction or disease (based on calculated creatinine clearance less than 30 mL/min/1.73 m2) at Screening.
• 11. Known or suspected unilateral or bilateral renal artery stenosis.
• 12. 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.
• 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 subjects with basal cell or Stage 1 squamous cell carcinoma of the skin.)
• 14. Type 1 or poorly controlled type 2 diabetes mellitus (glycosylated hemoglobin greater than 8.0%).
• 15. Hypo- or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory).
• 16. Alanine aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.
• 17. Upper arm circumference less than 24 cm or greater than 42 cm.
• 18. Works night (3rd) shift (defined as 11PM [2300] to 7AM [0700]).
• 19. Currently is participating in another investigational study or has participated in an investigational study within 30 days prior to randomization.
• 20. Study site employee, or is an immediate family member ( ie, spouse, parent, child, sibling) of a study site employee who is involved in conduct of this study.
• 21. 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.
• 22. Randomized in a previous azilsartan medoxomil study.

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/NCT00591773

Study ID Number: 01-05-TL-491-009

ClinicalTrials.gov Identifier: NCT00591773

Health Authority: United States: Food and Drug Administration

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