Clinical trial NCT00818883: Efficacy and Safety of Azilsartan Medoxomil and Chlorthalidone in Participants With Moderate to Severe Hypertension
Official title: A Phase 3, Double-Blind, Randomized, Efficacy and Safety Study of the TAK 491 Plus Chlorthalidone Fixed-Dose Combination Compared With TAK-491 and Hydrochlorothiazide Coadministration Therapy in Subjects With Moderate to Severe Essential Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Essential Hypertension
Keywords: Essential Hypertension
Hypertensive
Blood Pressure, High
Vascular Disease
Cardiovascular Disease
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2009-01-08
Enrollment: 609
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 chlorthalidone vs hydrochlorothiazide when each is used with azilsartan medoxomil, once daily (QD), in participants with moderate to severe essential 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. Despite the availability of antihypertensive agents, hypertension remains inadequately controlled; only about one-third of patients continue to maintain control successfully.

Although most antihypertensive agents are effective at the appropriate dose, the majority have side effects that limit their use. As a class, angiotensin II receptor blockers generally are considered more tolerable than other classes of antihypertensive agents. TAK-491 (azilsartan medoxomil) is an angiotensin II receptor blocker being evaluated by Takeda to treat essential hypertension.

Treatments for essential hypertension commonly include use of a thiazide-like diuretic, either alone or as part of combination treatment. Although chlorthalidone was commonly prescribed in the past, its use has widely been replaced with hydrochlorothiazide, presumably due to a lack of available combination products containing chlorthalidone, the assumption that hydrochlorothiazide and chlorthalidone have similar antihypertensive effects and cardiovascular benefits, and the perception that chlorthalidone use is associated with a greater frequency of hypokalemia. However, the frequency of hypokalemia with chlorthalidone use is relatively low in the dose range of 12.5 to 25 mg and these doses have been shown to be associated with potent blood pressure reduction. Several long-term outcomes trials have shown that blood pressure reductions associated with chlorthalidone treatment reduce risk of cardiovascular morbidity and mortality.

Most hypertensive patients require two or more agents to achieve target blood pressure and diuretics are commonly used in combination with other antihypertensive agents. This trial is designed to compare chlorthalidone and hydrochlorothiazide when coadministered with azilsartan medoxomil.

Participants in this study will receive either chlorthalidone or hydrochlorothiazide in combination with azilsartan medoxomil. Total commitment time for this study is about 13 weeks. Participants will be required to wear a blood pressure monitor for three 24 hours periods during the study.

Eligibility criteria: Inclusion Criteria:

1. Is treated with antihypertensive therapy and has a post-washout mean sitting clinic SBP greater than or equal to 160 and less than or equal to 190 mm Hg on Day -1; or the participant has not received antihypertensive treatment within 28 days prior to Screening and has a mean sitting clinic SBP greater than or equal to 160 and less than or equal to 190 mm Hg at the Screening Visit and on Day -1.
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 (clinical chemistry, hematology, and complete urinalysis) 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 (defined as 11 PM \[2300\] to 7 AM \[0700\]).
4. Has an upper arm circumference less than 24 cm or greater than 42 cm.
5. Is noncompliant (less than 70% or greater than 130%) with study medication during the placebo run-in period.
6. Has secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome).
7. Has a 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.
8. Has clinically significant cardiac conduction defects (ie, third-degree atrioventricular block, sick sinus syndrome, atrial fibrillation, or atrial flutter).
9. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
10. Has severe renal dysfunction or disease \[based on estimated glomerular filtration rate less than 30 mL/min/1.73m2 at Screening\].
11. Has known or suspected unilateral or bilateral renal artery stenosis.
12. Has a 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).
13. Has poorly-controlled type 1 or type 2 diabetes mellitus at Screening.
14. Has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory).
15. Has an alanine aminotransferase or aspartate aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.
16. 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.
17. Has known hypersensitivity to angiotensin II receptor blockers or thiazide-type diuretics or other sulfonamide-derived compounds.
18. Has been randomized in a previous azilsartan medoxomil study.
19. Currently participating in another investigational study or is receiving or has received any investigational compound within 30 days prior to Screening.
20. 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, Week 6 and Week 10.
Secondary outcomes:
measure: Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure
timeFrame: Baseline, Week 6 and Week 10.
measure: Change From Baseline in Mean Trough Systolic Blood Pressure (22 to 24 Hours After Dosing) as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 6 and Week 10.
measure: Change From Baseline in Mean Trough Diastolic Blood Pressure (22 to 24 Hours After Dosing) as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 6 and Week 10.
measure: Change From Baseline in 24-hour Mean Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 6 and Week 10.
measure: Change From Baseline in 24-hour Mean Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 6 and Week 10.
measure: Change From Baseline in the Mean Daytime (6 AM to 10 PM) Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 6 and Week 10.
measure: Change From Baseline in the Mean Daytime (6 AM to 10 PM) Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 6 and Week 10.
measure: Change From Baseline in the Mean Nighttime (12 AM to 6 AM) Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 6 and Week 10.
measure: Change From Baseline in the Mean Nighttime (12 AM to 6 AM) Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 6 and Week 10.
measure: Change From Baseline in the Mean Systolic Blood Pressure at 0 to 12 Hours After Dosing as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline, Week 6 and Week 10.
measure: Change From Baseline in the Mean Diastolic Blood Pressure at 0 to 12 Hours After Dosing as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 6 and Week 10.
measure: Percentage of Participants Who Reached Their Trough, Sitting, Clinic Systolic Blood Pressure Targets, Defined as <140 mm Hg for Participants Without Diabetes or Chronic Kidney Disease or <130 mm Hg for Participants With Diabetes or Chronic Kidney Disease
timeFrame: Week 2, Week 4, Week 6, Week 8 and Week 10.
measure: Percentage of Participants Who Reached Their Trough, Sitting, Clinic Diastolic Blood Pressure Target, Defined as <90 mm Hg for Participants Without Diabetes or Chronic Kidney Disease or <80 mm Hg for Participants With Diabetes or Chronic Kidney Disease.
timeFrame: Week 2, Week 4, Week 6, Week 8 and Week 10.
measure: Percentage of Participants Who Reached Their Trough, Sitting, Clinic Systolic and Diastolic Blood Pressure Targets, Defined as <140/90 mm Hg Without Diabetes or Chronic Kidney Disease or <130/80 mm Hg With Diabetes or Chronic Kidney Disease
timeFrame: Week 2, Week 4, Week 6, Week 8 and Week 10.
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Gulf Shores
country: United States
state: Alabama
city: Scottsboro
country: United States
state: Alabama
city: Gilbert
country: United States
state: Arizona
city: Sierra Vista
country: United States
state: Arizona
city: Paramount
country: United States
state: California
city: Sacramento
country: United States
state: California
city: San Diego
country: United States
state: California
city: Colorado Springs
country: United States
state: Colorado
city: Wheat Ridge
country: United States
state: Colorado
city: Milford
country: United States
state: Connecticut
city: Adventura
country: United States
state: Florida
city: Aventura
country: United States
state: Florida
city: Brooksville
country: United States
state: Florida
city: Crystal River
country: United States
state: Florida
city: DeLand
country: United States
state: Florida
city: Doral
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Naranja
country: United States
state: Florida
city: Sarasota
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: Atlanta
country: United States
state: Georgia
city: Stockbridge
country: United States
state: Georgia
city: Suwanee
country: United States
state: Georgia
city: Huntsville
country: United States
state: Illinois
city: Bloomington
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: 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: New Windsor
country: United States
state: New York
city: Asheboro
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Kettering
country: United States
state: Ohio
city: Downingtown
country: United States
state: Pennsylvania
city: Lancaster
country: United States
state: Pennsylvania
city: Lansdale
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Goose Creek
country: United States
state: South Carolina
city: Taylors
country: United States
state: South Carolina
city: Bryan
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Ettrick
country: United States
state: Virginia
city: Seattle
country: United States
state: Washington
city: Madison
country: United States
state: Wisconsin
city: Moscow
country: Russian Federation
city: Perm
country: Russian Federation
city: St. Petersburg
country: Russian Federation
Study officials:
affiliation: Takeda
name: Executive Medical Director
role: STUDY_DIRECTOR
References:
citation: Bakris GL, Sica D, White WB, Cushman WC, Weber MA, Handley A, Song E, Kupfer S. Antihypertensive efficacy of hydrochlorothiazide vs chlorthalidone combined with azilsartan medoxomil. Am J Med. 2012 Dec;125(12):1229.e1-1229.e10. doi: 10.1016/j.amjmed.2012.05.023. Epub 2012 Aug 30.