Clinical trial NCT00846365: Efficacy and Safety of Azilsartan Medoxomil Plus Chlorthalidone in Participants With Moderate to Severe Hypertension
Official title: A Phase 3, Double-Blind, Randomized, Efficacy and Safety Study Comparing the TAK-491 Plus Chlorthalidone Fixed-Dose Combination vs Benicar HCT® (Olmesartan Medoxomil-Hydrochlorothiazide) 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: 2009-02-18
Enrollment: 1085
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 determine the efficacy and safety of azilsartan medoxomil combined with chlorthalidone, 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. 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 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.

Participants in this study will be randomized to receive one of 3 possible dosing combinations of azilsartan medoxomil with either chlorthalidone or olmesartan medoxomil-hydrochlorothiazide over 8 weeks. The total duration of the study is approximately 13 weeks. Participants will make a total of 11 visits to the clinic, and will be required to participate in a follow-up telephone call 14 days after last dose of the study drug for adverse event assessment.

Eligibility criteria: Inclusion Criteria:

1. 190 mm Hg on Day -1 or if the participant has not received antihypertensive treatment within 28 days before 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 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 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 is on amlodipine or chlorthalidone.

Exclusion Criteria:

1. Has a mean sitting clinic diastolic blood pressure greater than 119 mm Hg.
2. Has a baseline 24-hour ambulatory blood pressure monitoring reading of insufficient quality.
3. Works a night (third) shift (from 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 with study medication during the placebo run-in period.
6. Has secondary hypertension of any etiology.
7. 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.
8. Has a clinically significant cardiac conduction.
9. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
10. Has severe renal dysfunction or disease.
11. Has a 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.
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 the participant according to the protocol.
17. Has a 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. Is currently participating in another investigational study or has participated in an investigational study or is receiving or has received any investigational compound within 30 days prior to Randomization.
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, Sitting, Clinic Systolic Blood Pressure.
timeFrame: Baseline and Week 8.
Secondary outcomes:
measure: Change From Baseline to Week 4 in Trough, Sitting, Clinic Systolic Blood Pressure.
timeFrame: Baseline and Week 4.
measure: Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure
timeFrame: Baseline, Week 4 and Week 8.
measure: Change From Baseline in Trough Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 4 and Week 8.
measure: Change From Baseline in Trough Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 4 and Week 8.
measure: Change From Baseline in 24-hour Mean Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 4 and Week 8.
measure: Change From Baseline in 24-hour Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 4 and Week 8.
measure: Change From Baseline in Daytime Mean (6am to 10pm) Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 4 and Week 8.
measure: Change From Baseline in Daytime Mean (6am to 10pm) Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 4 and Week 8.
measure: Change From Baseline in Nighttime Mean (12am to 6am) Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline, Week 4 and Week 8.
measure: Change From Baseline in Nighttime Mean (12am to 6am) Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 4 and Week 8.
measure: Change From Baseline in 12-hr Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 4 and Week 8.
measure: Change From Baseline in 12-hr Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.
timeFrame: Baseline, Week 4 and Week 8.
measure: Percentage of Participants Who Achieve a Clinic Systolic Blood Pressure Response, Defined as <140 mm Hg for Participants Without Diabetes or CKD or <130 mm Hg for Participants With Diabetes or CKD
timeFrame: Baseline, Week 2, Week 4, Week 6 and Week 8.
measure: Percentage of Participants Who Achieve a Clinic Diastolic Blood Pressure Response, Defined as Defined as <90 mm Hg for Participants Without Diabetes or CKD or <80 mm Hg for Participants With Diabetes or CKD
timeFrame: Baseline, Week 2, Week 4, Week 6 and Week 8.
measure: Percentage of Participants Who Achieve a Clinic Diastolic AND Systolic Blood Pressure Response, Defined as <140/90 mm Hg for Participants Without Diabetes or Chronic Kidney Disease (CKD) or <130/80 mm Hg for Participants With Diabetes or CKD
timeFrame: Baseline, Week 2, Week 4, Week 6 and Week 8.
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Haleyville
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state: Alabama
city: Hueytown
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state: Alabama
city: Jasper
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state: Alabama
city: Tallassee
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state: Alabama
city: Green Valley
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state: Arizona
city: Phoenix
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state: Arizona
city: Long Beach
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state: California
city: National City
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state: California
city: Roseville
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state: California
city: San Francisco
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state: California
city: San Jose
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state: California
city: Newark
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state: Delaware
city: Clearwater
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state: Florida
city: Jacksonville
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state: Florida
city: Jupiter
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state: Florida
city: Miami
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state: Florida
city: Ocala
country: United States
state: Florida
city: Pembroke Pines
country: United States
state: Florida
city: Plant City
country: United States
state: Florida
city: Tallahassee
country: United States
state: Florida
city: Arlington Heights
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state: Illinois
city: Chicago
country: United States
state: Illinois
city: Gurnee
country: United States
state: Illinois
city: Avon
country: United States
state: Indiana
city: Wichita
country: United States
state: Kansas
city: Louisville
country: United States
state: Kentucky
city: Auburn
country: United States
state: Maine
city: Baltimore
country: United States
state: Maryland
city: Brockton
country: United States
state: Massachusetts
city: Haverhill
country: United States
state: Massachusetts
city: North Dartmouth
country: United States
state: Massachusetts
city: Bingham Farms
country: United States
state: Michigan
city: Stevensville
country: United States
state: Michigan
city: Olive Branch
country: United States
state: Mississippi
city: Kansas City
country: United States
state: Missouri
city: New York
country: United States
state: New York
city: Burlington
country: United States
state: North Carolina
city: Charlotte
country: United States
state: North Carolina
city: Hickory
country: United States
state: North Carolina
city: Shelby
country: United States
state: North Carolina
city: Akron
country: United States
state: Ohio
city: Cleveland
country: United States
state: Ohio
city: Columbus
country: United States
state: Ohio
city: Marion
country: United States
state: Ohio
city: Middleburg Heights
country: United States
state: Ohio
city: Willoughby Hills
country: United States
state: Ohio
city: Norman
country: United States
state: Oklahoma
city: Bensalem
country: United States
state: Pennsylvania
city: Erie
country: United States
state: Pennsylvania
city: Reading
country: United States
state: Pennsylvania
city: Cranston
country: United States
state: Rhode Island
city: Cumberland
country: United States
state: Rhode Island
city: North Charleston
country: United States
state: South Carolina
city: Jackson
country: United States
state: Tennessee
city: Kingsport
country: United States
state: Tennessee
city: Milan
country: United States
state: Tennessee
city: Austin
country: United States
state: Texas
city: Corpus Christi
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Arlington
country: United States
state: Virginia
city: Burke
country: United States
state: Virginia
city: Charlottesville
country: United States
state: Virginia
city: Manassas
country: United States
state: Virginia
city: Lakewood
country: United States
state: Washington
city: Port Orchard
country: United States
state: Washington
city: Menomonee Falls
country: United States
state: Wisconsin
city: Temuco
country: Chile
state: Cautín
city: La Serena
country: Chile
state: Elqui
city: Vina del Mar
country: Chile
state: Valparaíso
city: Osorno
country: Chile
city: Santiago
country: Chile
city: Tijuana
country: Mexico
state: Baja California
city: Leon
country: Mexico
state: Guanajuato
city: Guadalajara
country: Mexico
state: Jalisco
city: Chihuahua
country: Mexico
city: San Luis Potosi
country: Mexico
Study officials:
affiliation: Takeda
name: Executive Medical Director
role: STUDY_DIRECTOR
References:
citation: Cushman WC, Bakris GL, White WB, Weber MA, Sica D, Roberts A, Lloyd E, Kupfer S. A randomized titrate-to-target study comparing fixed-dose combinations of azilsartan medoxomil and chlorthalidone with olmesartan and hydrochlorothiazide in stage-2 systolic hypertension. J Hypertens. 2018 Apr;36(4):947-956. doi: 10.1097/HJH.0000000000001647.