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”

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.

Study Type: Interventional

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

Study Primary Completion Date: May 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 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. Subjects participating in this study will be required to discontinue their current antihypertensive medication, and will be randomized to receive either 20 mg or 40 mg of TAK-491, 160 mg of valsartan, 20 mg of olmesartan or a placebo for two weeks.

At the end of 2 weeks, dosage will increase to 40 mg and 80 mg of TAK-491, 320 mg of valsartan and 40 mg of olmesartan respectively. Subjects will remain at the higher dosage for the remaining four weeks of the study.

Intervention(s) in this Clinical Trial

• Drug: TAK-491
  • TAK-491 20 mg tablet, orally, once daily for two weeks, increased to 40 mg tablet, orally, once daily for four weeks.
• Drug: TAK-491
  • TAK-491 40 mg tablet, orally, once daily for two weeks, increased to 80 mg (two 40 mg tablets) orally, once daily for four weeks.
• Drug: Valsartan
  • Valsartan 160 mg capsule, orally, once daily for two weeks, increased to 320 mg (two 160 mg capsules) orally, once daily for four weeks.
• Drug: Olmesartan
  • Olmesartan 20 mg capsule, orally, once daily for two weeks, increased to 40 mg (two 20 mg capsules) orally, once daily for four weeks..
• Drug: Placebo
  • Placebo tablets and placebo capsules, orally, once daily for six weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Experimental: 2
• Active Comparator: 3
• Active Comparator: 4
• Placebo Comparator: 5

Primary Measures

• The change in 24-hour mean systolic blood pressure by ambulatory blood pressure monitoring.
  • Time Frame: Weeks: 0 and 6.
    Safety Issue?: No

Secondary Measures

• 24-hour mean diastolic blood pressure by ambulatory blood pressure monitoring.
  • Time Frame: Weeks: 0 and 6.
    Safety Issue?: No
• Sitting trough clinic systolic blood pressure and diastolic blood pressure.
  • Time Frame: Weeks: 0, 2, 4 and 6.
    Safety Issue?: No
• Systolic and diastolic blood pressure using additional ambulatory blood pressure monitoring parameters (daytime mean [6 AM to 10 PM], nighttime mean [12 AM to 6 AM].
  • Time Frame: Weeks: 0 and 6 (blood pressure mean at 0 - 12 hours after dosing, and trough mean at 22 to 24 hours after dosing).
    Safety Issue?: No
• Safety endpoints (adverse events and vital signs).
  • Time Frame: Weeks: 0, 2, 4 and 6.
    Safety Issue?: No
• Safety endpoints (electrocardiograms)
  • Time Frame: Week 6.
    Safety Issue?: No
• Safety endpoints (safety laboratory tests: hematology, chemistry, and urinalysis tests)
  • Time Frame: Weeks: 0, 2 and 6.
    Safety Issue?: No

Inclusion Criteria:

• The subject has essential hypertension (defined as sitting trough clinic SBP between 150 and 180 mm Hg) and 24-hour mean systolic blood pressure between 130 and 170 mm
• Hg.
• The subject has clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory or the results are deemed not clinically significant for inclusion into this study by the investigator.
• The subject is 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:

• The subject has sitting trough clinic diastolic blood pressure greater than 114 mm
• Hg.
• The subject has a baseline 24-hour ambulatory blood pressure monitoring reading of insufficient quality.
• The subject is taking or expected to take an excluded medication including:
• Antihypertensive agents
• Insulin.
• Other agents that alter blood pressure including:
• 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 >325 mg/day or cyclooxygenase-2 inhibitors.
• Systemic use of corticosteroids (topical or inhaled is acceptable).
• Thiazolidinediones.
• The subject is hypersensitive to angiotensin II receptor blockers.
• The subject has a history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.
• The subject has clinically significant cardiac conduction defects (eg, 3rd degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation, or flutter).
• The subject has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
• The subject has secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, or Cushing syndrome).
• The subject has moderate to severe renal dysfunction or disease (confirmed by calculated creatinine clearance <30 mL/min/1.73m2) at Screening.
• Subject has known or suspected unilateral or bilateral renal artery stenosis.
• The subject has a history of drug or alcohol abuse within the past 2 years.
• The subject 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. (This criterion does not apply to those subjects with basal cell or stage I squamous cell carcinoma of the skin).
• The subject has type 1 or poorly-controlled type 2 diabetes mellitus (hemoglobin A1c
• >8.0%) at Screening.
• The subject has hyperkalemia as defined by the central laboratory normal reference range at Screening.
• The subject has an alanine aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice at Screening.
• The subject has an upper arm circumference less than 24 cm or greater than 42 cm.
• The subject works night (3rd) shift (defined as 11 PM [2300] to 7 AM [0700]).
• If female, the subject is pregnant, intends to become pregnant during the course of the study, or is lactating.
• The subject currently is participating in another investigational study or has participated in an investigational study within 30 days prior to Randomization.
• The subject has 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.
• The subject has been randomized in a previous TAK-491 study.

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

Stuart Kupfer, MD Study Director Takeda Global Research & Development Center, Inc.  

Overall Contact: Kenya Barber 224-554-5252 kbarber@tgrd.com

Information obtained from ClinicalTrials.gov on September 04, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00696436

Study ID Number: 01-06-TL-491-019

ClinicalTrials.gov Identifier: NCT00696436

Health Authority: United States: Food and Drug Administration