Efficacy and Safety of Azilsartan Medoxomil and Chlorthalidone in Participants With Moderate to Severe Hypertension

NCT ID: NCT00818883

Last Updated: 2012-02-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 609 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-02-28
• Study Completion Date: 2009-11-30

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.

Conditions

Essential Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD

Group Type: EXPERIMENTAL

Azilsartan medoxomil and chlorthalidone

Intervention Type: DRUG

Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablet, orally, once daily and hydrochlorothiazide placebo-matching tablets, orally, once daily for up to 10 weeks.

For participants who do not achieve target blood pressure by Week 6, the dose of chlorthalidone will be increased for the remaining 4 weeks of treatment.

Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD

Group Type: EXPERIMENTAL

Azilsartan medoxomil and hydrochlorothiazide

Intervention Type: DRUG

Azilsartan medoxomil 40 mg, tablets, orally, once daily and hydrochlorothiazide 12.5 mg, tablets, orally, once daily for up to 10 weeks.

For participants who do not achieve target blood pressure by Week 6, the dose of hydrochlorothiazide will be increased for the remaining 4 weeks of treatment.

Interventions

Azilsartan medoxomil and chlorthalidone

Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablet, orally, once daily and hydrochlorothiazide placebo-matching tablets, orally, once daily for up to 10 weeks.

For participants who do not achieve target blood pressure by Week 6, the dose of chlorthalidone will be increased for the remaining 4 weeks of treatment.

Intervention Type: DRUG

Azilsartan medoxomil and hydrochlorothiazide

Azilsartan medoxomil 40 mg, tablets, orally, once daily and hydrochlorothiazide 12.5 mg, tablets, orally, once daily for up to 10 weeks.

For participants who do not achieve target blood pressure by Week 6, the dose of hydrochlorothiazide will be increased for the remaining 4 weeks of treatment.

Intervention Type: DRUG

Other Intervention Names

TAK-491; TAK-491CLD; TAK-491; TAK-491CLD

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Executive Medical Director

Role: STUDY_DIRECTOR

Takeda

Locations

Birmingham, Alabama, United States

Gulf Shores, Alabama, United States

Scottsboro, Alabama, United States

Gilbert, Arizona, United States

Sierra Vista, Arizona, United States

Paramount, California, United States

Sacramento, California, United States

San Diego, California, United States

Colorado Springs, Colorado, United States

Wheat Ridge, Colorado, United States

Milford, Connecticut, United States

Adventura, Florida, United States

Aventura, Florida, United States

Brooksville, Florida, United States

Crystal River, Florida, United States

DeLand, Florida, United States

Doral, Florida, United States

Miami, Florida, United States

Naranja, Florida, United States

Sarasota, Florida, United States

Tampa, Florida, United States

West Palm Beach, Florida, United States

Winter Haven, Florida, United States

Atlanta, Georgia, United States

Stockbridge, Georgia, United States

Suwanee, Georgia, United States

Huntsville, Illinois, United States

Bloomington, Indiana, United States

Valparaiso, Indiana, United States

Crestview Hills, Kentucky, United States

Lexington, Kentucky, United States

West Yarmouth, Massachusetts, United States

Ann Arbor, Michigan, United States

City of Saint Peters, Missouri, United States

St Louis, Missouri, United States

New Windsor, New York, United States

Asheboro, North Carolina, United States

Cincinnati, Ohio, United States

Kettering, Ohio, United States

Downingtown, Pennsylvania, United States

Lancaster, Pennsylvania, United States

Lansdale, Pennsylvania, United States

Pittsburgh, Pennsylvania, United States

Goose Creek, South Carolina, United States

Taylors, South Carolina, United States

Bryan, Texas, United States

San Antonio, Texas, United States

Ettrick, Virginia, United States

Seattle, Washington, United States

Madison, Wisconsin, United States

Moscow, , Russia

Perm, , Russia

Saint Petersburg, , Russia

Countries

United States; Russia

References

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.

Reference Type: DERIVED

PMID: 22939358 (View on PubMed)

Other Identifiers

U1111-1112-7119

Identifier Type: REGISTRY

Identifier Source: secondary_id

TAK-491CLD_306

Identifier Type: -

Identifier Source: org_study_id