Clinical trial NCT00847626: Efficacy and Safety of Azilsartan Medoxomil Combined With Chlorthalidone in Participants With Moderate to Severe Hypertension
Official title: A Phase 3, Double-Blind, Randomized, Factorial, Efficacy and Safety Study of TAK 491 Plus Chlorthalidone Fixed-Dose Combination in Participants With Moderate to Severe Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypertension
Keywords: Hypertensive
Blood Pressure, High
Vascular Disease
Cardiovascular Disease
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2009-02-19
Enrollment: 1711
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the efficacy and safety of azilsartan medoxomil combined with chlorthalidone, once daily (QD), in participants with moderate to severe hypertension.

Detailed description: According to the World Health Organization (WHO), 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.

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 that is 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.

This study is designed to compare the antihypertensive effect and the safety and tolerability of the azilsartan medoxomil plus chlorthalidone fixed-dose combination product (TAK 491CLD FDC) with azilsartan monotherapy and chlorthalidone monotherapy during 8 weeks of treatment.

Participants in this study will be randomized to receive one of 11 possible dosing combinations of azilsartan medoxomil , chlorthalidone and placebo over an 8 week period. The total duration of the study will be approximately 13 weeks. Participants will make 12 visits to the clinic. Each participant will also be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

1. Is treated with antihypertensive therapy and has a post-washout mean sitting clinic systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm Hg on the day prior to randomization, or the participant has not received antihypertensive treatment within 28 days prior to Screening and has a mean sitting clinic systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm Hg at the Screening Visit and on the day prior to randomization.
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 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 on Day -28 if on amlodipine or chlorthalidone.

Exclusion Criteria:

1. Has a mean sitting clinic diastolic blood pressure greater than 119 mm Hg on the day prior to randomization.
2. Has a baseline 24-hour ambulatory blood pressure measurement reading of insufficient quality.
3. Has 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. Has is noncompliant with study medication during the placebo run-in period.
6. Has secondary hypertension of any etiology.
7. Has recent history 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.
9. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
10. Has severe renal dysfunction or disease.
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.
13. Has poorly controlled type 1 or type 2 diabetes mellitus at Screening.
14. Has hypokalemia or hyperkalemia.
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 Has according to the protocol.
17. Has known hypersensitivity to angiotensin II receptor blockers, thiazide-type diuretics or other sulfonamide-derived compounds.
18. Has been randomized in a previous azilsartan medoxomil study.
19. Is 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 to Week 8 in Trough, Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring (Pooled Analysis)
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in Trough, Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring (Pairwise Analysis)
timeFrame: Baseline and Week 8.
Secondary outcomes:
measure: Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in Trough Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring in Black Participants (Pooled Analysis)
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in Trough Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring in Black Participants (Pairwise Analysis)
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in Trough, Sitting, Clinic Diastolic Blood Pressure
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in the Mean Trough Diastolic Blood Pressure (22 to 24 Hours After Dosing), as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in the 24-hour Mean Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in the 24-hour Mean Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in the Mean Daytime (6 AM to 10 PM) Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in the Mean Daytime (6 AM to 10 PM) Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in the Mean Nighttime (12 AM to 6 AM) Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in the Mean Nighttime (12 AM to 6 AM) Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in the Mean Systolic Blood Pressure at 0 to 12 Hours After Dosing, as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the Mean Diastolic Blood Pressure at 0 to 12 Hours After Dosing, as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline and Week 8.
measure: Percentage of Participants Who Achieve a Clinic Systolic Blood Pressure Response at Week 8, as Defined by Clinic Systolic Blood Pressure <140 mm Hg and/or a Reduction of ≥20 mm Hg From Baseline.
timeFrame: Baseline and Week 8
measure: Percentage of Participants Who Achieve a Clinic Diastolic Blood Pressure Response at Week 8, Defined as Clinic Diastolic Blood Pressure <90 mm Hg and/or a Reduction of ≥10 mm Hg From Baseline.
timeFrame: Baseline and Week 8.
measure: Percentage of Participants Who Achieve Both a Clinic Systolic and Diastolic Blood Pressure Response at Week 8.
timeFrame: Baseline and Week 8.
Other outcomes:
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city: Hialeah
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city: Miami
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city: Ocala
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city: Ormond Beach
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city: St Petersburg
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city: Atlanta
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state: Georgia
city: Buffalo Grove
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state: Illinois
city: Libertyville
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state: Illinois
city: Melrose Park
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state: Illinois
city: Fishers
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state: Indiana
city: Indianapolis
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state: Indiana
city: Erlanger
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state: Kentucky
city: Madisonville
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state: Kentucky
city: Paducah
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state: Kentucky
city: Rockville
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state: Maryland
city: Ann Arbor
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state: Michigan
city: Chesterfield
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state: Michigan
city: St Louis
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state: Missouri
city: Omaha
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state: Nebraska
city: Henderson
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state: Nevada
city: Brick
country: United States
state: New Jersey
city: Margate
country: United States
state: New Jersey
city: Albuquerque
country: United States
state: New Mexico
city: Endwell
country: United States
state: New York
city: Cary
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state: North Carolina
city: Winston-Salem
country: United States
state: North Carolina
city: Cincinnati
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state: Ohio
city: Cleveland
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state: Ohio
city: Columbus
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city: Dayton
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city: Lyndhurst
country: United States
state: Ohio
city: Willoughby Hills
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state: Ohio
city: Oklahoma City
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state: Oklahoma
city: Ashland
country: United States
state: Oregon
city: Altoona
country: United States
state: Pennsylvania
city: Bensalem
country: United States
state: Pennsylvania
city: Feasterville
country: United States
state: Pennsylvania
city: Jenkintown
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state: Pennsylvania
city: Sellersville
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state: Pennsylvania
city: Warminster
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state: Pennsylvania
city: Charleston
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state: South Carolina
city: Florence
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state: South Carolina
city: Murrells Inlet
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state: South Carolina
city: Simpsonville
country: United States
state: South Carolina
city: Spartanburg
country: United States
state: South Carolina
city: Clarksville
country: United States
state: Tennessee
city: New Tazewell
country: United States
state: Tennessee
city: Austin
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state: Texas
city: Bellaire
country: United States
state: Texas
city: Dallas
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state: Texas
city: Houston
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state: Texas
city: McKinney
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state: Texas
city: Richardson
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state: Texas
city: San Antonio
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state: Texas
city: Magna
country: United States
state: Utah
city: West Jordan
country: United States
state: Utah
city: Arlington
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state: Virginia
city: Virginia Beach
country: United States
state: Virginia
city: Oregon
country: United States
state: Wisconsin
city: Santiago
country: Chile
city: Temuco
country: Chile
city: Aguascalientes
country: Mexico
city: Merida
country: Mexico
city: Mexico DF
country: Mexico
city: Bellavista
country: Peru
city: Chiclayo
country: Peru
city: Jesus Maria
country: Peru
city: Miraflores
country: Peru
city: San Borja
country: Peru
city: San Martin de Porres
country: Peru
city: Trujillo
country: Peru
city: Umacollo
country: Peru
city: Moscow
country: Russian Federation
city: St. Petersburg
country: Russian Federation
Study officials:
affiliation: Takeda
name: Executive Medical Director
role: STUDY_DIRECTOR
References: