Efficacy and Safety of Azilsartan Medoxomil and Chlorthalidone Compared to Olmesartan Medoxomil and Hydrochlorothiazide in Participants With Moderate to Severe Hypertension.

Official Title: “A Phase 3b, Double-Blind, Randomized, 12-Week Efficacy and Safety Study Comparing the TAK-491 Plus Chlorthalidone Fixed-Dose Combination vs Olmesartan Medoxomil-Hydrochlorothiazide in Subjects With Moderate to Severe Hypertension”

The purpose of this study is to compare the antihypertensive effect of azilsartan medoxomil plus chlorthalidone, once daily (QD), to olmesartan medoxomil plus hydrochlorothiazide in participants with moderate to severe hypertension.

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. As the population ages, the prevalence of hypertension will continue to increase if broad and effective preventive measures are not implemented. Despite the availability of antihypertensive agents, hypertension remains inadequately controlled; only about one third of patients continue to maintain control successfully.

Treatment algorithms for essential hypertension commonly include thiazides or thiazide-like diuretics, either alone or as part of combination treatment. Chlorthalidone is a commercially available, orally administered thiazide-type diuretic agent.

TAK-491 (azilsartan medoxomil) is an angiotensin II receptor blocker developed by Takeda to treat participants with essential hypertension.

This study will compare the safety and tolerability of azilsartan medoxomil plus chlorthalidone (TAK-491CLD) fixed-dose combination to olmesartan medoxomil plus hydrochlorothiazide fixed-dose combination.

Intervention(s) in this Clinical Trial

• Drug: Azilsartan medoxomil and chlorthalidone
  • Azilsartan medoxomil 20 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily and olmesartan and hydrochlorothiazide placebo-matching tablets, orally, once daily for up to 4 weeks. Participants will be force titrated at Week 4 to azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily for the next 4 weeks. Participants will then be force titrated at Week 8 to azilsartan medoxomil 40 mg and chlorthalidone 25 mg combination tablets, orally, once daily for the next 4 weeks.
• Drug: Azilsartan medoxomil and chlorthalidone
  • Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily and olmesartan and hydrochlorothiazide placebo-matching tablets, orally, once daily for up to 4 weeks. Participants will be force titrated at Week 4 to azilsartan medoxomil 80 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily for the next 4 weeks. Participants will then be force titrated at Week 8 to azilsartan medoxomil 80 mg and chlorthalidone 25 mg combination tablets, orally, once daily for the next 4 weeks.
• Drug: Olmesartan medoxomil and hydrochlorothiazide
  • Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablets, orally, once daily and azilsartan medoxomil and chlorthalidone placebo-matching tablets, orally, once daily for up to 4 weeks. Participants will be force titrated at Week 4 to olmesartan medoxomil 40 mg and hydrochlorothiazide 12.5 mg combination tablets, orally, once daily for the next 4 weeks. Participants will then be force titrated at Week 8 to olmesartan medoxomil 40 mg and hydrochlorothiazide 25 mg combination tablets, orally, once daily for the next 4 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Azilsartan Medoxomil 20-40mg/Chlorthalidone 12.5-25mg QD
• Experimental: Azilsartan Medoxomil 40-80mg/Chlorthalidone 12.5-25mg QD
• Active Comparator: Olmesartan Medoxomil 20-40mg/Hydrochlorothiazide 12.5-25mg QD

Primary Measures

• Change From Baseline in Trough, Sitting, Clinic Systolic Blood Pressure.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No

Secondary Measures

• Change From Baseline in Trough, Sitting, Clinic Systolic Blood Pressure.
  • Time Frame: Baseline, Week 4 and Week 8.
    Safety Issue?: No
• Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure.
  • Time Frame: Baseline, Week 4, Week 8 and Week 12.
    Safety Issue?: No
• Change From Baseline in Mean Trough Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in Mean Trough Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in 24-hour Mean Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in 24-hour Mean Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in Mean Daytime (6 AM to 10 PM) Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in Mean Daytime (6 AM to 10 PM) Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in Mean Nighttime (12 AM to 6 AM) Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in Mean Nighttime (12 AM to 6 AM) Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in the Mean Systolic Blood Pressure at 0 to 12 Hours After Dosing by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in the Mean Diastolic Blood Pressure at 0 to 12 Hours After Dosing by Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in the Mean Systolic Blood Pressure During Each Hour of the 24-hour Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in the Mean Diastolic Blood Pressure During Each Hour of the 24-hour Ambulatory Blood Pressure Monitoring.
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Percentage of Participants Who Reached Target Clinic Systolic Blood Pressure of <140 mm Hg and/or Reduction of ≥20 mm Hg From Baseline.
  • Time Frame: Baseline, Week 4, Week 8 and Week 12.
    Safety Issue?: No
• Percentage of Participants Who Reached Target Clinic Diastolic Blood Pressure of <90 mm Hg and/or Reduction of ≥10 mm Hg From Baseline.
  • Time Frame: Baseline, Week 4, Week 8 and Week 12.
    Safety Issue?: No
• Percent of Participants Who Reached Target Clinic Systolic Blood Pressure of <140 mm Hg and/or Reduction of ≥20 mm Hg From Baseline and Target Clinic Diastolic Blood Pressure of <90 mm Hg and/or Reduction of ≥10 mm Hg From Baseline.
  • Time Frame: Baseline, Week 4, Week 8 and Week 12.
    Safety Issue?: No

Inclusion Criteria:

• 1. Has a mean sitting clinic systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm Hg.
• 2. Females of childbearing potential who are sexually active agree to routinely use adequate contraception from Screening through 30 days after the last administered study drug dose.
• 3. Has clinical laboratory test results within the reference range for the testing laboratory or the investigator does not consider the results to be clinically significant.
• 4. Is willing to discontinue current antihypertensive medications on Day -21 or Day -28 if the participant is on amlodipine or chlorthalidone.

Exclusion Criteria:

• 1. Has a mean sitting clinic diastolic blood pressure greater than 119 mm Hg on Day -1.
• 2. Has a baseline 24-hour ambulatory blood pressure monitoring reading of insufficient quality.
• 3. Works a night (third) shift.
• 4. Has an upper arm circumference less than 24 cm or greater than 42 cm.
• 5. Has secondary hypertension of any etiology.
• 6. Has a recent history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.
• 7. Has clinically significant cardiac conduction defects.
• 8. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
• 9. Has severe renal dysfunction or disease.
• 10. Has known or suspected unilateral or bilateral renal artery stenosis.
• 11. Has a history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug.
• 12. Has poorly-controlled diabetes mellitus at Screening.
• 13. Has hypokalemia or hyperkalemia.
• 14. Has an alanine aminotransferase or aspartate aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.
• 15. Has any other known serious disease or condition that would compromise safety, might affect life expectancy, or make it difficult to successfully manage and follow the participant according to the protocol.
• 16. Has known hypersensitivity to angiotensin II receptor blockers or thiazide-type diuretics or other sulfonamide-derived compounds.
• 17. Has a history of drug abuse or a history of alcohol abuse within the past 2 years.

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

Sr VP 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/NCT01033071

Study ID Number: TAK-491CLD_303

ClinicalTrials.gov Identifier: NCT01033071

Health Authority: United States: Food and Drug Administration

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