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

Information source: Takeda
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Essential Hypertension

Intervention: Azilsartan medoxomil and chlorthalidone (Drug); Azilsartan medoxomil and chlorthalidone (Drug); Olmesartan medoxomil-hydrochlorothiazide (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Takeda

Official(s) and/or principal investigator(s):
Executive Medical Director, Study Director, Affiliation: Takeda

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.

Clinical Details

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure.

Secondary outcome:

Change From Baseline to Week 4 in Trough, Sitting, Clinic Systolic Blood Pressure.

Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure

Change From Baseline in Trough Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.

Change From Baseline in Trough Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.

Change From Baseline in 24-hour Mean Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.

Change From Baseline in 24-hour Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.

Change From Baseline in Daytime Mean (6am to 10pm) Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.

Change From Baseline in Daytime Mean (6am to 10pm) Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.

Change From Baseline in Nighttime Mean (12am to 6am) Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring

Change From Baseline in Nighttime Mean (12am to 6am) Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.

Change From Baseline in 12-hr Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.

Change From Baseline in 12-hr Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.

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

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

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

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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Locations and Contacts

Osorno, Chile

Santiago, Chile

Chihuahua, Mexico

San Luis Potosi, Mexico

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

Tijuana, Baja California, Mexico

Long Beach, California, United States

National City, California, United States

Roseville, California, United States

San Francisco, California, United States

San Jose, California, United States

Temuco, Cautín, Chile

Newark, Delaware, United States

La Serena, Elqui, Chile

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

Leon, Guanajuato, Mexico

Arlington Heights, Illinois, United States

Chicago, Illinois, United States

Gurnee, Illinois, United States

Avon, Indiana, United States

Guadalajara, Jalisco, Mexico

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

Vina del Mar, Valparaíso, Chile

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

Additional Information

EDARBYCLOR Package Insert

FDA Safety Alerts and Recalls

Starting date: March 2009
Last updated: February 9, 2012

Page last updated: August 23, 2015

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