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: August 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.

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.

Intervention(s) in this Clinical Trial

• Drug: TAK-491
  • TAK-491 20 mg, tablets, orally, TAK-491 40 mg placebo-matching tablets, orally, TAK-491 80 mg placebo-matching tablets, orally and Valsartan 160 mg/Olmesartan 20 mg placebo-matching capsules, orally, once daily for two weeks. Increased to TAK-491 40 mg, tablets, orally, TAK-491 20 mg placebo-matching tablets, orally, TAK-491 80 mg placebo-matching tablets, orally and Valsartan 160 mg/Olmesartan 20 mg placebo-matching capsules, orally, once daily for up to four weeks.
• Drug: TAK-491
  • TAK-491 40 mg, tablets, orally, TAK-491 20 mg placebo-matching tablets, orally, TAK-491 80 mg placebo-matching tablets, orally and Valsartan 160 mg/Olmesartan 20 mg placebo-matching capsules, orally, once daily for two weeks. Increased to TAK-491 80 mg, tablets, orally, TAK-491 20 mg placebo-matching tablets, orally, TAK-491 40 mg placebo-matching tablets, orally and Valsartan 160 mg/Olmesartan 20 mg placebo-matching capsules, orally, once daily for up to four weeks.
• Drug: Valsartan
  • Valsartan 160 mg, capsules, orally, TAK-491 20 mg placebo-matching tablets, orally, TAK-491 40 mg placebo-matching tablets, orally and TAK-491 80 mg placebo-matching tablets, orally, once daily for two weeks. Increased to Valsartan 320 mg, capsules, orally, TAK-491 20 mg placebo-matching tablets, orally, TAK-491 40 mg placebo-matching tablets, orally and TAK-491 80 mg placebo-matching tablets, orally, once daily for up to four weeks.
• Drug: Olmesartan
  • Olmesartan 20 mg, capsules, orally, TAK-491 20 mg placebo-matching tablets, orally, TAK-491 40 mg placebo-matching tablets, orally and TAK-491 80 mg placebo-matching tablets, orally, once daily for two weeks. Increased to Olmesartan 40 mg, capsules, orally, TAK-491 20 mg placebo-matching tablets, orally, TAK-491 40 mg placebo-matching tablets, orally and TAK-491 80 mg placebo-matching tablets, orally, once daily for up to four weeks.
• Drug: Placebo
  • TAK-491 20 mg placebo-matching tablets, orally, TAK-491 40 mg placebo-matching tablets, orally, TAK-491 80 mg placebo-matching tablets, orally, and Valsartan 160 mg/320 mg/Olmesartan 20 mg/40mg placebo-matching capsules, orally, once daily for up to 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

• Change from Baseline in the 24-hour mean systolic blood pressure by ambulatory blood pressure monitoring.
  • Time Frame: Week 6 or Final Visit
    Safety Issue?: No

Secondary Measures

• Change from baseline in sitting trough clinic systolic blood pressure and diastolic blood pressure.
  • Time Frame: Weeks 1, 2, 4 and 6 or Final Visit
    Safety Issue?: No
• 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).
  • Time Frame: Week 6 or Final Visit
    Safety Issue?: No
• Change from baseline in 24-hour mean diastolic blood pressure using ambulatory blood pressure monitoring
  • Time Frame: Week 6 or Final Visit
    Safety Issue?: No
• Adverse Events
  • Time Frame: Weeks 1, 2, 4 and 6 or Final Visit
    Safety Issue?: Yes
• Vital Signs
  • Time Frame: Weeks 1, 2, 4 and 6 or Final Visit
    Safety Issue?: Yes
• Electrocardiograms
  • Time Frame: Week 6 or Final Visit
    Safety Issue?: Yes
• Safety Laboratory Tests (Hematology, Serum Chemistry and Urinalysis)
  • Time Frame: Weeks 2 and 6 or Final Visit
    Safety Issue?: Yes

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.

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.  

Overall Contact: Takeda Study Registration Call Center 800-778-2860 medicalinformation@tpna.com

Information obtained from ClinicalTrials.gov on July 02, 2009

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