Clinical trial NCT01033071: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Essential Hypertension
Keywords: Hypertensive
Blood Pressure, High
Cardiovascular disease
Vascular Disease
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2009-12-16
Enrollment: 1071
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in Trough, Sitting, Clinic Systolic Blood Pressure.
timeFrame: Baseline and Week 12.
Secondary outcomes:
measure: Change From Baseline in Trough, Sitting, Clinic Systolic Blood Pressure.
timeFrame: Baseline, Week 4 and Week 8.
measure: Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure.
timeFrame: Baseline, Week 4, Week 8 and Week 12.
measure: Change From Baseline in Mean Trough Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Change From Baseline in Mean Trough Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Change From Baseline in 24-hour Mean Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Change From Baseline in 24-hour Mean Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Change From Baseline in Mean Daytime (6 AM to 10 PM) Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Change From Baseline in Mean Daytime (6 AM to 10 PM) Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Change From Baseline in Mean Nighttime (12 AM to 6 AM) Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Change From Baseline in Mean Nighttime (12 AM to 6 AM) Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Change From Baseline in the Mean Systolic Blood Pressure at 0 to 12 Hours After Dosing by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Change From Baseline in the Mean Diastolic Blood Pressure at 0 to 12 Hours After Dosing by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Change From Baseline in the Mean Systolic Blood Pressure During Each Hour of the 24-hour Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Change From Baseline in the Mean Diastolic Blood Pressure During Each Hour of the 24-hour Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 12.
measure: Percentage of Participants Who Reached Target Clinic Systolic Blood Pressure of <140 mm Hg and/or Reduction of ≥20 mm Hg From Baseline.
timeFrame: Baseline, Week 4, Week 8 and Week 12.
measure: Percentage of Participants Who Reached Target Clinic Diastolic Blood Pressure of <90 mm Hg and/or Reduction of ≥10 mm Hg From Baseline.
timeFrame: Baseline, Week 4, Week 8 and Week 12.
measure: 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.
timeFrame: Baseline, Week 4, Week 8 and Week 12.
Other outcomes:
Locations:
city: Gulf Shores
country: United States
state: Alabama
city: Litchfield Park
country: United States
state: Arizona
city: Mesa
country: United States
state: Arizona
city: Scottsdale
country: United States
state: Arizona
city: Tucson
country: United States
state: Arizona
city: Buena Park
country: United States
state: California
city: Carmichael
country: United States
state: California
city: Greenbrae
country: United States
state: California
city: Irvine
country: United States
state: California
city: Paramount
country: United States
state: California
city: Sacramento
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state: California
city: San Diego
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Spring Valley
country: United States
state: California
city: Wildomar
country: United States
state: California
city: Colorado Springs
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state: Colorado
city: Milford
country: United States
state: Connecticut
city: Waterbury
country: United States
state: Connecticut
city: Newark
country: United States
state: Delaware
city: Aventura
country: United States
state: Florida
city: Clearwater
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state: Florida
city: Deland
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state: Florida
city: Fort Lauderdale
country: United States
state: Florida
city: Miami
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state: Florida
city: Ocala
country: United States
state: Florida
city: Plant City
country: United States
state: Florida
city: Tallahassee
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: West Palm beach
country: United States
state: Florida
city: Winter Haven
country: United States
state: Florida
city: Dunwoody
country: United States
state: Georgia
city: Roswell
country: United States
state: Georgia
city: Suwanee
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Melrose Park
country: United States
state: Illinois
city: Naperville
country: United States
state: Illinois
city: Avon
country: United States
state: Indiana
city: Indianapolis
country: United States
state: Indiana
city: Valparaiso
country: United States
state: Indiana
city: Crestview Hills
country: United States
state: Kentucky
city: Lexington
country: United States
state: Kentucky
city: Auburn
country: United States
state: Maine
city: Brockton
country: United States
state: Massachusetts
city: Hyannis
country: United States
state: Massachusetts
city: West Yarmouth
country: United States
state: Massachusetts
city: Ann Arbor
country: United States
state: Michigan
city: St Louis
country: United States
state: Missouri
city: St Peters
country: United States
state: Missouri
city: Henderson
country: United States
state: Nevada
city: Margate
country: United States
state: New Jersey
city: Wildwood Crest
country: United States
state: New Jersey
city: Albuquerque
country: United States
state: New Mexico
city: Glens Falls
country: United States
state: New York
city: Boiling Springs
country: United States
state: North Carolina
city: Raleigh
country: United States
state: North Carolina
city: Salisbury
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Columbus
country: United States
state: Ohio
city: Willoughby Hills
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Yukon
country: United States
state: Oklahoma
city: Ashland
country: United States
state: Oregon
city: Portland
country: United States
state: Oregon
city: Bensalem
country: United States
state: Pennsylvania
city: Feasterville
country: United States
state: Pennsylvania
city: Lansdale
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Reading
country: United States
state: Pennsylvania
city: Tipton
country: United States
state: Pennsylvania
city: Cranston
country: United States
state: Rhode Island
city: Cumberland
country: United States
state: Rhode Island
city: Mt Pleasant
country: United States
state: South Carolina
city: Simpsonville
country: United States
state: South Carolina
city: Beaumont
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: North Richland Hills
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Magna
country: United States
state: Utah
city: Manassas
country: United States
state: Virginia
city: Lakewood
country: United States
state: Washington
city: Port Orchard
country: United States
state: Washington
city: Madison
country: United States
state: Wisconsin
city: Menomonee Falls
country: United States
state: Wisconsin
city: Abbotsford
country: Canada
state: British Columbia
city: Powell River
country: Canada
state: British Columbia
city: Mount Pearl
country: Canada
state: Newfoundland and Labrador
city: Halifax
country: Canada
state: Nova Scotia
city: London
country: Canada
state: Ontario
city: Ottawa
country: Canada
state: Ontario
city: Sarnia
country: Canada
state: Ontario
city: Vaughan
country: Canada
state: Ontario
city: Whitby
country: Canada
state: Ontario
city: Woodstock
country: Canada
state: Ontario
Study officials:
affiliation: Takeda
name: Sr VP Clinical Science
role: STUDY_DIRECTOR
References:
citation: Cushman WC, Bakris GL, White WB, Weber MA, Sica D, Roberts A, Lloyd E, Kupfer S. Azilsartan medoxomil plus chlorthalidone reduces blood pressure more effectively than olmesartan plus hydrochlorothiazide in stage 2 systolic hypertension. Hypertension. 2012 Aug;60(2):310-8. doi: 10.1161/HYPERTENSIONAHA.111.188284. Epub 2012 Jun 18.