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

NCT ID: NCT00846365

Last Updated: 2012-03-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1085 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-03-31
• Study Completion Date: 2010-06-30

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.

Conditions

Essential Hypertension

Study Design

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

Study Groups

Azilsartan Medoxomil 20-40mg plus Chlorthalidone 12.5-25 mg QD

(dependant on blood pressure)

Group Type: EXPERIMENTAL

Azilsartan medoxomil and chlorthalidone

Intervention Type: DRUG

Azilsartan medoxomil 20 mg and chlorthalidone 12.5 mg, tablets, orally, and olmesartan medoxomil-hydrochlorothiazide placebo tablets once daily for 8 weeks.

If participant does not achieve target blood pressure at Week 4, then the dosage will be increased to azilsartan medoxomil 40 mg and chlorthalidone 25 mg, tablets, orally, once daily for the remaining 4 weeks.

Azilsartan Medoxomil 40-80mg plus Chlorthalidone 12.5-25 mg QD

(dependant on blood pressure)

Group Type: EXPERIMENTAL

Azilsartan medoxomil and chlorthalidone

Intervention Type: DRUG

Azilsartan medoxomil 40 mg and chlorthalidone 12.5, mg, tablets, orally, and olmesartan medoxomil-hydrochlorothiazide placebo tablets once daily for 8 weeks.

If participant does not achieve target blood pressure at Week 4, then the dosage will be increased to azilsartan medoxomil 80 mg and chlorthalidone 25 mg, tablets, orally, once daily for the remaining 4 weeks.

Olmesartan medoxomil 20-40mg/hydrochlorothiazide 12.5-25mg QD

(dependant on blood pressure)

Group Type: ACTIVE_COMPARATOR

Olmesartan medoxomil-hydrochlorothiazide

Intervention Type: DRUG

Olmesartan medoxomil 20 mg/hydrochlorothiazide 12.5 mg, tablets, orally, and Azilsartan medoxomil and chlorthalidone placebo-matching tablets, orally, once daily for 8 weeks.

If participant does not achieve target blood pressure at Week 4, then the dosage will be increased to olmesartan medoxomil 40 mg/hydrochlorothiazide 25 mg, tablets, orally, once daily for the remaining 4 weeks.

Interventions

Azilsartan medoxomil and chlorthalidone

Azilsartan medoxomil 20 mg and chlorthalidone 12.5 mg, tablets, orally, and olmesartan medoxomil-hydrochlorothiazide placebo tablets once daily for 8 weeks.

If participant does not achieve target blood pressure at Week 4, then the dosage will be increased to azilsartan medoxomil 40 mg and chlorthalidone 25 mg, tablets, orally, once daily for the remaining 4 weeks.

Intervention Type: DRUG

Azilsartan medoxomil and chlorthalidone

Azilsartan medoxomil 40 mg and chlorthalidone 12.5, mg, tablets, orally, and olmesartan medoxomil-hydrochlorothiazide placebo tablets once daily for 8 weeks.

If participant does not achieve target blood pressure at Week 4, then the dosage will be increased to azilsartan medoxomil 80 mg and chlorthalidone 25 mg, tablets, orally, once daily for the remaining 4 weeks.

Intervention Type: DRUG

Olmesartan medoxomil-hydrochlorothiazide

Olmesartan medoxomil 20 mg/hydrochlorothiazide 12.5 mg, tablets, orally, and Azilsartan medoxomil and chlorthalidone placebo-matching tablets, orally, once daily for 8 weeks.

If participant does not achieve target blood pressure at Week 4, then the dosage will be increased to olmesartan medoxomil 40 mg/hydrochlorothiazide 25 mg, tablets, orally, once daily for the remaining 4 weeks.

Intervention Type: DRUG

Other Intervention Names

azilsartan medoxomil; chlorthalidone; TAK-491; TAK-491CLD; azilsartan medoxomil; chlorthalidone; TAK-491; TAK-491CLD; Benicar HCT®

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.

• 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

Haleyville, Alabama, United States

Hueytown, Alabama, United States

Jasper, Alabama, United States

Tallassee, Alabama, United States

Green Valley, Arizona, United States

Phoenix, Arizona, United States

Long Beach, California, United States

National City, California, United States

Roseville, California, United States

San Francisco, California, United States

San Jose, California, United States

Newark, Delaware, United States

Clearwater, Florida, United States

Jacksonville, Florida, United States

Jupiter, Florida, United States

Miami, Florida, United States

Ocala, Florida, United States

Pembroke Pines, Florida, United States

Plant City, Florida, United States

Tallahassee, Florida, United States

Arlington Heights, Illinois, United States

Chicago, Illinois, United States

Gurnee, Illinois, United States

Avon, Indiana, United States

Wichita, Kansas, United States

Louisville, Kentucky, United States

Auburn, Maine, United States

Baltimore, Maryland, United States

Brockton, Massachusetts, United States

Haverhill, Massachusetts, United States

North Dartmouth, Massachusetts, United States

Bingham Farms, Michigan, United States

Stevensville, Michigan, United States

Olive Branch, Mississippi, United States

Kansas City, Missouri, United States

New York, New York, United States

Burlington, North Carolina, United States

Charlotte, North Carolina, United States

Hickory, North Carolina, United States

Shelby, North Carolina, United States

Akron, Ohio, United States

Cleveland, Ohio, United States

Columbus, Ohio, United States

Marion, Ohio, United States

Middleburg Heights, Ohio, United States

Willoughby Hills, Ohio, United States

Norman, Oklahoma, United States

Bensalem, Pennsylvania, United States

Erie, Pennsylvania, United States

Reading, Pennsylvania, United States

Cranston, Rhode Island, United States

Cumberland, Rhode Island, United States

North Charleston, South Carolina, United States

Jackson, Tennessee, United States

Kingsport, Tennessee, United States

Milan, Tennessee, United States

Austin, Texas, United States

Corpus Christi, Texas, United States

Dallas, Texas, United States

Houston, Texas, United States

San Antonio, Texas, United States

Salt Lake City, Utah, United States

Arlington, Virginia, United States

Burke, Virginia, United States

Charlottesville, Virginia, United States

Manassas, Virginia, United States

Lakewood, Washington, United States

Port Orchard, Washington, United States

Menomonee Falls, Wisconsin, United States

Temuco, Cautín, Chile

La Serena, Elqui, Chile

Osorno, Osorno, Chile

Viña del Mar, Región de Valparaíso, Chile

Santiago, Santiago Metropolitan, Chile

Chihuahua City, Chihuahua, Mexico

Tijuana, Estado de Baja California, Mexico

León, Guanajuato, Mexico

Guadalajara, Jalisco, Mexico

San Luis Potosí City, San Luis Potosí, Mexico

Countries

United States; Chile; Mexico

References

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.

Reference Type: DERIVED

PMID: 29334491 (View on PubMed)

Other Identifiers

U1111-1112-4287

Identifier Type: OTHER

Identifier Source: secondary_id

TAK-491CLD_301

Identifier Type: -

Identifier Source: org_study_id