An Efficacy and Safety Study of TAK-491 Compared to Valsartan and Olmesartan in Subjects With Essential Hypertension.

Condition(s) targeted: Essential Hypertension

Intervention: TAK-491 (Drug); TAK-491 (Drug); Valsartan (Drug); Olmesartan (Drug); Placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Takeda Global Research & Development Center, Inc.

Official(s) and/or principal investigator(s):
Executive Medical Director Clinical Science, Study Director, Affiliation: Takeda Global Research & Development Center, Inc.

Overall contact:
Takeda Study Registration Call Center, Phone: 800-778-2860, Email: medicalinformation@tpna.com

The purpose of this study is to evaluate the efficacy and safety of TAK-491 compared to valsartan and olmesartan in subjects with essential hypertension.

Official title: A Double-Blind, Randomized, Placebo-Controlled, 5-Arm Titration Study to Evaluate the Efficacy and Safety of TAK-491 When Compared With Valsartan and Olmesartan in Subjects With Essential Hypertension

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study

Primary outcome: Change from Baseline in the 24-hour mean systolic blood pressure by ambulatory blood pressure monitoring.

Secondary outcome:

Change from baseline in sitting trough clinic systolic blood pressure and diastolic blood pressure.

Change from baseline in systolic and diastolic blood pressure using additional ambulatory blood pressure monitoring parameters (daytime mean 6am-10pm, nighttime mean 12am-6am, BP mean 0-12 hours post dosing, and trough mean 22-24 hours post dosing).

Change from baseline in 24-hour mean diastolic blood pressure using ambulatory blood pressure monitoring

Adverse Events

Vital Signs

Electrocardiograms

Safety Laboratory Tests (Hematology, Serum Chemistry and Urinalysis)

Detailed description: Hypertension affects approximately 50 million individuals in the United States. As the population ages, the prevalence of hypertension will continue to increase if broad and effective preventive measures are not implemented. 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 treatments, hypertension remains inadequately controlled: only about one-third of patients successfully maintain control.

A major component of blood pressure regulation is the renin-angiotensin-aldosterone system. This is a system of hormone-mediated feedback interactions that result in the relaxation or constriction of blood vessels in response to various stimuli. Angiotensin II, a polypeptide hormone, is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme as part of the renin-angiotensin-aldosterone system. Angiotensin II is the principal pressor agent of the renin-angiotensin-aldosterone system and has multiple effects on the cardiovascular system and on electrolyte homeostasis.

Drugs that modulate the renin-angiotensin-aldosterone system are used commonly worldwide for the treatment of hypertension. Of these, some block the synthesis of angiotensin II by inhibiting angiotensin-converting enzyme, while others inhibit the action of angiotensin II by binding directly to the angiotensin II type 1 receptor (angiotensin II receptor blockers), thereby allowing blood vessels to dilate, resulting in a reduction in blood pressure. The effects of angiotensin II receptor blockers on other conditions in which the renin-angiotensin-aldosterone system plays a significant role, such as congestive heart failure, postmyocardial infarction management, and diabetic nephropathy are also are being investigated.

Although most antihypertensive agents are effective at the appropriate dose, the majority have side effects that limit their use. Angiotensin-converting enzyme inhibitors are commonly associated with cough, and more rarely, with angioedema. β-blockers are associated with fatigue and erectile dysfunction; calcium antagonists with peripheral edema; and diuretics with metabolic complications. As a class, angiotensin II receptor blockers are generally considered more tolerable than other classes of antihypertensive agents, although there is still a need for compounds with improved tolerability and efficacy for the treatment of hypertension.

TAK-491 is an angiotensin II type 1 receptor antagonist currently being tested as a treatment for essential hypertension.

Study participation is anticipated to be about 10 weeks. Multiple procedures will occur at each visit which may include fasting, blood collection, urine collection, physical examinations, electrocardiograms and ambulatory blood pressure monitoring. Outside of the study center, participants will be required wear an ambulatory blood pressure monitoring device at 24 hour intervals.

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

Criteria:

Inclusion Criteria:

- Essential hypertension (sitting systolic blood pressure between 150 and 180 mm Hg,

inclusive, at Day - 1 and 24-hour mean systolic blood pressure between 130 and 170 mm

Hg, inclusive, at Day 1).

- Capable of understanding and complying with protocol requirements.

- 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

- Clinical laboratory evaluations within the reference range for the testing laboratory

or the results are deemed not clinically significant for inclusion into this study by the investigator.

- Willing to discontinue current antihypertensive medications at Screening Day 21

visit. If the subject is on amlodipine prior to Screening, the subject is willing to

discontinue this medication at Screening Day - 28.

Exclusion Criteria:

- Sitting diastolic blood pressure greater than 114 mm Hg at Day -1 (day prior to

Randomization).

- Baseline 24-hour ambulatory blood pressure monitor reading of insufficient quality.

- Taking or expected to take an excluded medication as described in the Excluded

Medications.

- Hypersensitive to angiotensin II receptor blockers.

- History of myocardial infarction, heart failure, unstable angina, coronary artery

bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.

- Clinically significant cardiac conduction defects.

- Hemodynamically significant left ventricular outflow obstruction due to aortic

valvular disease.

- Secondary hypertension of any etiology.

- Noncompliant (less than 70% or greater than 130%) with study medication during run-in

period.

- Moderate to severe renal dysfunction or disease.

- Known or suspected unilateral or bilateral renal artery stenosis.

- History of drug or alcohol abuse within the past 2 years.

- Previous 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 subjects with basal cell or stage I squamous cell carcinoma of the skin).

- Type 1 or poorly-controlled type 2 diabetes mellitus (glycosylate hemoglobin greater

than 8. 0%) at Screening.

- Hyperkalemia as defined by the central laboratory normal reference range at

Screening.

- Alanine aminotransferase level of greater than 2. 5 times the upper limit of normal,

active liver disease, or jaundice at Screening.

- Upper arm circumference less than 24 cm or greater than 42 cm.

- Works night (3rd) shift (defined as 11 PM [2300] to 7 AM [0700]).

- Unwilling or unable to comply with the protocol or scheduled appointments.

- Currently is participating in another investigational study or has participated in an

investigational study within 30 days prior to Randomization.

- Any other serious disease or condition at Screening or Randomization that would

compromise subject safety, might affect life expectancy, or make it difficult to successfully manage and follow the subject according to the protocol.

- Has been randomized in a previous TAK-491 study.

- Is required to take or continues taking any disallowed medication, prescription

medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

- Insulin.

- Tricyclic antidepressants.

- Atypical antipsychotic agents.

- Monoamine oxidase inhibitors.

- Lithium.

- Phosphodiesterase type 5 inhibitors.

- Diet medications.

- Amphetamines or their derivatives.

- Chronically used (defined as more than 3 doses per week) common cold medications

or nonsteroidal anti-inflammatory, including aspirin greater than 325 mg per day or cyclooxygenase 2 inhibitors.

- Systemic use of corticosteroids (topical or inhaled is acceptable).

- Thiazolidinediones.

Takeda Study Registration Call Center, Phone: 800-778-2860, Email: medicalinformation@tpna.com

Bahía Blanca, Argentina; Recruiting

Berazategui, Argentina; Recruiting

Buenos Aires, Argentina; Recruiting

Corrientes, Argentina; Recruiting

Haedo Pcia. de Buenos Aires, Argentina; Recruiting

Jujuy, Argentina; Recruiting

La Plata, Argentina; Recruiting

Ramos Mejía Pcia. de Buenos Aires, Argentina; Recruiting

Rosario, Argentina; Recruiting

Salta, Argentina; Recruiting

San Miguel de Tucumán, Argentina; Recruiting

Córdoba, Argentina; Recruiting

Belo Horizonte, Brazil; Recruiting

Campinas, Brazil; Recruiting

Fortaleza, Brazil; Recruiting

Goiaenia, Brazil; Recruiting

Joildille, Brazil; Recruiting

Porto Alegre, Brazil; Recruiting

Rio Janeiro, Brazil; Recruiting

Sao Paulo, Brazil; Recruiting

Sorocava, Brazil; Recruiting

Mexico City, Mexico; Recruiting

Querètaro, Mexico; Recruiting

Aguascalientes, Mexico; Recruiting

Chihuahua, Mexico; Recruiting

San Luis Potosí, Mexico; Recruiting

Huaura, Peru; Recruiting

Arequipa, Peru; Recruiting

Cusco, Peru; Recruiting

Ica, Peru; Recruiting

Lima, Peru; Recruiting

Trujillo, Peru; Recruiting

Aguas Buenas, Puerto Rico; Recruiting

Carolina, Puerto Rico; Recruiting

Jardines de Loiza, Puerto Rico; Recruiting

Orocovis, Puerto Rico; Recruiting

Ponce, Puerto Rico; Recruiting

San Juan, Puerto Rico; Recruiting

Alabaster, Alabama, United States; Terminated

Ozark, Alabama, United States; Recruiting

Litchfield Park, Arizona, United States; Recruiting

Mesa, Arizona, United States; Recruiting

Tempe, Arizona, United States; Recruiting

Green Valley, Arizona, United States; Recruiting

Tijuana, Baja California, Mexico; Recruiting

Carmichael, California, United States; Recruiting

Chula Vista, California, United States; Recruiting

Lincoln, California, United States; Recruiting

National City, California, United States; Recruiting

Pasadena, California, United States; Recruiting

Riverside, California, United States; Recruiting

Sacramento, California, United States; Recruiting

San Diego, California, United States; Recruiting

San Dimas, California, United States; Recruiting

San Ramon, California, United States; Recruiting

Santa Ana, California, United States; Recruiting

Vista, California, United States; Recruiting

Mission Viejo, California, United States; Recruiting

San Fransisco, California, United States; Recruiting

Colorado Springs, Colorado, United States; Recruiting

Denver, Colorado, United States; Recruiting

Littleton, Colorado, United States; Recruiting

Longmont, Colorado, United States; Recruiting

Carlos Paz, Córdoba, Argentina; Recruiting

Miami, Florida, United States; Recruiting

New Port Richey, Florida, United States; Recruiting

New Smyrna Beach, Florida, United States; Terminated

Tallahassee, Florida, United States; Recruiting

Cape Coral, Florida, United States; Active, not recruiting

Largo, Florida, United States; Recruiting

Palm Harbor, Florida, United States; Recruiting

Clearwater, Florida, United States; Recruiting

Dunwoody, Georgia, United States; Recruiting

Roswell, Georgia, United States; Recruiting

León, Guanajuato, Mexico; Recruiting

Arlington Heights, Illinois, United States; Recruiting

Belleville, Illinois, United States; Recruiting

Champaign, Illinois, United States; Recruiting

Chicago, Illinois, United States; Recruiting

Peoria, Illinois, United States; Recruiting

Vernon Hills, Illinois, United States; Recruiting

Evansville, Indiana, United States; Recruiting

Indianapolis, Indiana, United States; Recruiting

Terre Haute, Indiana, United States; Recruiting

Guadalajara, Jalapa, Mexico; Recruiting

Overland Park, Kansas, United States; Recruiting

Kansas City, Kansas, United States; Not yet recruiting

Shawnee, Kansas, United States; Recruiting

Biddeford, Maine, United States; Recruiting

Norwood, Maine, United States; Active, not recruiting

Baltimore, Maryland, United States; Recruiting

Towson, Maryland, United States; Recruiting

Guaymayen, Mendoza, Argentina; Recruiting

Brooklyn Center, Minnesota, United States; Recruiting

Chesterfield, Missouri, United States; Recruiting

Jefferson City, Missouri, United States; Recruiting

Kansas City, Missouri, United States; Recruiting

St Louis, Missouri, United States; Recruiting

Billings, Montana, United States; Recruiting

Las Vegas, Nevada, United States; Recruiting

Margate, New Jersey, United States; Recruiting

Glens Falls, New York, United States; Recruiting

New Windsor, New York, United States; Recruiting

New York, New York, United States; Recruiting

Great Neck, New York, United States; Active, not recruiting

New Hyde Park, New York, United States; Recruiting

Charlotte, North Carolina, United States; Recruiting

Raleigh, North Carolina, United States; Recruiting

Monterrey, Nuevo Leon, Mexico; Recruiting

Columbus, Ohio, United States; Recruiting

Norman, Oklahoma, United States; Recruiting

Tulsa, Oklahoma, United States; Recruiting

Yukon, Oklahoma, United States; Recruiting

Ashland, Oregon, United States; Recruiting

Eugene, Oregon, United States; Terminated

Medford, Oregon, United States; Recruiting

Portland, Oregon, United States; Recruiting

Tipton, Pennsylvania, United States; Recruiting

Pittsburgh, Pennsylvania, United States; Recruiting

Charleston, South Carolina, United States; Recruiting

Murrells Inlet, South Carolina, United States; Recruiting

North Charleston, South Carolina, United States; Recruiting

Cleveland, Tennessee, United States; Recruiting

Bedford, Texas, United States; Recruiting

Dallas, Texas, United States; Recruiting

Houston, Texas, United States; Recruiting

Missouri City, Texas, United States; Recruiting

San Antonio, Texas, United States; Recruiting

Sugarland, Texas, United States; Recruiting

Xalapa, Veracruz, Mexico; Recruiting

Tacoma, Washington, United States; Recruiting

Starting date: April 2008
Ending date: May 2009
Last updated: January 20, 2009