Official Title: “An 8-Month Phase 3, Open-Label Study With a Blinded Reversal Phase to Evaluate the Safety and Tolerability of TAK-491 in Subjects With Essential Hypertension”

The purpose of this study is to determine the long term safety and tolerability of TAK-491 in 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: April 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.

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. AII is the principal pressor agent of the renin-angiotensin-aldosterone system with a myriad of effects on the cardiovascular system and on electrolyte homeostasis. Two receptors for angiotensin II have been identified. Angiotensin II type 1 (AT1) receptors are located predominantly in vascular smooth muscle, where activation by angiotensin II results in vasoconstriction, hypertrophic proliferation, and inflammation. In contrast, stimulation of angiotensin II type 2 (AT2) receptors by angiotensin II results in vasodilation, antiproliferative effects, and other effects that are opposite from those of AT1 receptor stimulation.

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 inhibitors, while others inhibit the action of angiotensin II by binding directly to the AT1 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, post-myocardial infarction management, and diabetic nephropathy, also are being investigated.

TGRD is developing TAK-491 to treat mild to moderate essential hypertension. Nonclinical studies have indicated that TAK-491 is an antagonist of the AT1 receptor subtype.

This study consists of 2 phases. The first phase will be a 26-week, open-label, multicenter phase to evaluate the safety and tolerability of TAK-491 in subjects with essential hypertension. Following 26 weeks of open-label treatment, subjects will then start a 6-week,double-blind reversal phase to evaluate the efficacy of TAK-491. At double-blind randomization, subjects will discontinue open-label TAK-491 and be randomized to receive either TAK-491 at their current dose, or placebo.

Study participation is anticipated to be about 8.5 Months. Multiple procedures will occur at each visit which may include fasting, blood collection, urine collection, vital signs including sitting and standing blood pressure and pulse, body height and weight, physical examinations and electrocardiograms.

Intervention(s) in this Clinical Trial

• Drug: TAK-491
  • TAK-491 40 mg (titrated to 80 mg or 20 mg as appropriate), tablets, orally, once daily with or without chlortiadone, 25 mg, tablets, orally, once daily as needed and other antihypertensive medications as needed for 26 weeks. At week 26, TAK-491 20 mg to 80 mg (current dose), tablets, orally, once daily with or without chlortiadone 25 mg (if currently taking), tablets, orally, once daily for up to 6 weeks.
• Drug: Placebo
  • TAK-491 40 mg (titrated to 80 mg or 20 mg as appropriate), tablets, orally, once daily with or without chlortiadone, 25 mg, tablets, orally once daily and other antihypertensive medications as needed for 26 weeks. At week 26, TAK-491 placebo-matching tablets, orally, once daily with or without chlortiadone 25 mg (if currently taking), tablets, orally, once daily for up to 6 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Placebo Comparator: 2

Primary Measures

• Change from Baseline in sitting clinic diastolic blood pressure.
  • Time Frame: Week 32 or Final Visit.
    Safety Issue?: No

Secondary Measures

• Change from Baseline in sitting clinic systolic blood pressure.
  • Time Frame: Week 32 or Final Visit.
    Safety Issue?: No

Inclusion Criteria

• Has essential hypertension (diastolic blood pressure greater than or equal to 95mm Hg and less than or equal to 119 mm Hg. For subjects with diabetes or chronic kidney disease diastolic blood pressure must be greater than or equal to 85 mm Hg and less than or equal to 109 mm Hg.
• Female subject is not of childbearing potential (eg, sterilized, postmenopausal).
• Female subjects 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 (including clinical chemistry, hematology, and complete urinalysis) are within the reference range for the testing laboratory unless the results are deemed not clinically significant for inclusion into this study by the investigator.

Exclusion Criteria

• Systolic blood pressure greater than 185 mm Hg.
• Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:
• 1. AII receptor blockers other than the study drug.
• 2. Taking more than 2 antihypertensive agents.
• Is hypersensitive to AII receptor blockers.
• Recent history (within the last 6 months) of myocardial infarction, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, cerebrovascular accident, or transient ischemic attack.
• History of moderate to severe heart failure or hypertensive encephalopathy.
• Has clinically significant cardiac conduction defects (eg, third-degree atrioventricular block, sick sinus syndrome).
• Has secondary hypertension of any etiology.
• Known or suspected unilateral or bilateral renal artery stenosis.
• Has severe renal dysfunction or disease (based on calculated creatinine clearance less than 30 mL/min/1.73 m2) at Screening.
• History of drug abuse (defined as illicit drug use) or a history of alcohol abuse (defined as an average consumption of more than 2 alcoholic drinks per day) within the past 2 years.
• 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 include those subjects with basal cell or stage 1 squamous cell carcinoma of the skin).
• Has uncontrolled diabetes mellitus with poor glucose control at screening based on hemoglobin glycosylated hemoglobin greater than 8.5%.
• Alanine aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.
• Serum potassium level of greater than the upper limit of normal, per the central laboratory reference ranges.
• Currently is participating in another investigational study or has participated in an investigational study within 30 days prior to enrollment.
• Study site employee, or is an immediate family member (ie, spouse, parent, child, sibling) of a study site employee who is involved in conduct of this study.
• Any other serious disease or condition at screening (or enrollment) 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.

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

VP Clinical Science Strategy 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/NCT00696384

Study ID Number: 01-06-TL-491-016

ClinicalTrials.gov Identifier: NCT00696384

Health Authority: United States: Food and Drug Administration