Official Title: “A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of TAK-491 When Co-Administered With Amlodipine 5 mg in Subjects With Essential Hypertension”

The purpose of this study is to evaluate the effectiveness and safety of TAK-491 in African-American subjects with essential hypertension.

Study Type: Interventional

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

Study Primary Completion Date: March 2009

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 continue to maintain control successfully.

A major component of blood pressure regulation is the renin-angiotensin-aldosterone system, a system of hormone-mediated feedback interactions that results 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 with a myriad of effects on the cardiovascular system and on electrolyte homeostasis.

Takeda Global Research & Development Center, Inc. is developing TAK-491 to treat patients with essential hypertension. TAK-491 is a prodrug that is hydrolyzed to the active moiety, TAK-536, which is a selective antagonist of the angiotensin II type 1 receptor subtype.

Amlodipine is a slow-channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. It is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

This study is being conducted to determine whether administration of TAK-491 in combination with amlodipine in subjects with uncontrolled hypertension is more efficacious in reducing systolic blood pressure than amlodipine alone. Participation in this study is anticipated to be approximately 10 weeks.

Intervention(s) in this Clinical Trial

• Drug: TAK-491
  • TAK-491 40 mg, tablets, orally, once daily and amlodipine 5 mg, tablets, orally, once daily for up to 6 weeks.
• Drug: TAK-491
  • TAK-491 80 mg, tablets, orally, once daily and amlodipine 5 mg, tablets, orally, once daily for up to 6 weeks.
• Drug: Amlodipine
  • TAK-491 placebo-matching tablets, orally, once daily and amlodipine 5 mg, tablets, orally, once daily for up to 6 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Experimental: 2
• Active Comparator: 3

Primary Measures

• Change from baseline to Week 6 in the 24-hour mean systolic blood pressure by ambulatory blood pressure monitor.
  • Time Frame: Week 6
    Safety Issue?: No

Secondary Measures

• Change from baseline to Week 6 in trough clinic sitting systolic blood pressure.
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline to Week 6 in the 24-hour mean diastolic blood pressure by ambulatory blood pressure monitor.
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline to Week 6 in trough clinic sitting diastolic blood pressure.
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for daytime mean (6am to 10pm) systolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for daytime mean (6am to 10pm) diastolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for nighttime mean (12am to 6am) systolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for nighttime mean (12am to 6am) diastolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for 0-12-hr mean systolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for 0-12-hr mean diastolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for trough mean (22-24-hr) systolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for trough mean (22-24-hr) diastolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Proportion of subjects who achieve a Clinic Diastolic Blood Pressure Response, defined as less than 90 mm Hg and/or reduction from baseline of greater than or equal to 10 mm Hg
  • Time Frame: Week 6
    Safety Issue?: No
• Proportion of subjects who achieve a Clinic Systolic Blood Pressure Response, defined as less than 140 mm Hg and/or reduction from baseline of greater than or equal to 20 mm Hg
  • Time Frame: Week 6
    Safety Issue?: No
• Proportion of subjects who achieve both a Clinic Diastolic and Systolic Blood Pressure Response
  • Time Frame: Week 6
    Safety Issue?: No

Inclusion Criteria:

• Has essential hypertension and 24-hour mean systolic blood pressure greater than or equal to 140 mm Hg and less than or equal to 180 mm Hg.
• 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
• Has 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.
• Is willing to discontinue current antihypertensive medications.

Exclusion Criteria:

• Has sitting trough clinic diastolic blood pressure greater than 119 mm Hg.
• Has a baseline 24 hour ambulatory blood pressure monitoring reading of insufficient quality.
• The subject is hypersensitive to angiotensin II receptor blockers or calcium channel blockers.
• 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.
• Has clinically significant cardiac conduction defects.
• Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
• Has secondary hypertension of any etiology
• Is non-compliant with study medication during placebo run-in period.
• Has severe renal dysfunction or disease.
• Has known or suspected unilateral or bilateral renal artery stenosis.
• Has a history of drug abuse or a history of alcohol abuse within the past 2 years.
• Has a previous history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug.
• Has type 1 or poorly controlled type 2 diabetes mellitus.
• Has hyperkalemia as defined by the central laboratory normal reference range,
• Has an alanine aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease or jaundice.
• Has an upper arm circumference less than 24 cm or greater than 42 cm.
• Works night (3rd) shift.
• Currently participating in another investigational study or has participated in an investigational study within 30 days prior to randomization.
• Has any other serious disease or condition that would compromise subject safety 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:
• Amlodipine
• Antihypertensive agents
• Insulin
• Tricyclic antidepressants
• Monoamine oxidase inhibitors
• Lithium
• Phosphodiesterase type 5 inhibitors
• Diet medications
• Amphetamines or their derivatives
• Chronically used common cold medications
• Chronically used nonsteroidal anti-inflammatory including aspirin greater than 325 mg/day or cyclooxygenase-2 inhibitors
• Systemic use of corticosteroids
• Thiazolidinediones
• Atypical antipsychotic agents

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Takeda Global Research & Development Center, Inc.

Overall Clinical Trial Officials and Contacts

Executive Medical Director Clinical Science Study Director Takeda Global Research & Development Center, Inc.  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00591266

Study ID Number: 01-05-TL-491-010

ClinicalTrials.gov Identifier: NCT00591266

Health Authority: United States: Food and Drug Administration