A Safety and Tolerability Study of Azilsartan Medoxomil in Participants With Essential Hypertension

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 azilsartan medoxomil, once daily (QD), in participants with Essential Hypertension.

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.

Takeda Global Research & Development Center, Inc. is developing TAK-491 (azilsartan medoxomil) to treat mild to moderate essential hypertension. Nonclinical studies have indicated that azilsartan medoxomil 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 participants with essential hypertension. Investigators were instructed to manage participants according to a protocol-specified treatment algorithm to achieve target blood pressure. All participants who completed the open-label phase then were randomized into a 6-week double-blind, placebo-controlled (azilsartan medoxomil [maintained at the final dose from the open-label phase] or placebo, in addition to their current other antihypertensive medications including chlorthalidone, as applicable) reversal phase to evaluate maintenance/durability of azilsartan medoxomil -mediated blood pressure reduction, as well as potential rebound following the cessation of azilsartan medoxomil.

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: Azilsartan medoxomil
  • All subjects initiated azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks, force-titrated to 80 mg, tablets, orally, once daily. After Week 8, chlorthalidone, 25 mg, tablets, orally, once daily as needed and other antihypertensive medications as needed to achieve target blood pressure (defined as <140/90 mm Hg for participants without diabetes or chronic kidney disease (CKD) and <130/80 mm Hg for participants with diabetes or CKD) for up to 26 weeks. Study medication could have been up-titrated only after the subject had been at the previous dose level for a minimum of 2 weeks. Study medication could only have been up- or down-titrated by 1 dose level per scheduled or unscheduled visit.
• Drug: Azilsartan medoxomil, with or without chlorthalidone and other non-angiotensin II receptor blocker antihypertensive medications.
  • Azilsartan medoxomil at the final dose received during the open-label phase: (20 mg, 40 mg or 80 mg), tablets, orally, once daily with or without chlorthalidone 25 mg, tablets, orally once daily and other non-ARB antihypertensive medications (if currently taking), for 6 weeks/Week 32.
• Drug: Placebo
  • Azilsartan medoxomil placebo-matching tablets, orally, once daily with or without chlorthalidone 25 mg or other non-ARB antihypertensive (if currently taking), tablets, orally, once daily for 6 weeks/Week 32.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Azilsartan Medoxomil QD-Open Label Phase (Baseline - Week 26)
• Experimental: Azilsartan Medoxomil QD - Double-Blind Phase (Week 26-32)
• Placebo Comparator: Placebo QD - Double-Blind Phase (Week 26- 32)

Primary Measures

• Change From Double-blind Baseline (Week 26) in Sitting Clinic Diastolic Blood Pressure to Week 32
  • Time Frame: Double-blind Baseline (Week 26) and Week 32.
    Safety Issue?: No

Secondary Measures

• Change From Double-blind Baseline (Week 26) in Sitting Clinic Systolic Blood Pressure to Week 32
  • Time Frame: Double-blind Baseline (Week 26) and Week 32.
    Safety Issue?: No
• Change From Open Label Baseline (Week 0) in Sitting Clinic Diastolic Blood Pressure to Week 26
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Change From Open Label Baseline (Week 0) in Sitting Clinic Systolic Blood Pressure to Week 26
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Number of Participants With Adverse Events During the Open-Label Phase
  • Time Frame: Baseline to Week 26
    Safety Issue?: Yes
• Number of Participants With Adverse Events in the Double-Blind Baseline Phase
  • Time Frame: Double-blind Baseline/Week 26 to Week 32
    Safety Issue?: Yes

Inclusion Criteria

• 1. Has essential hypertension (diastolic blood pressure ≥ 95mm Hg and ≤ 119 mm Hg. For participants with diabetes or chronic kidney disease diastolic blood pressure must be ≥ 85 mm Hg and ≤ to 109 mm Hg.
• 2. Female participant is not of childbearing potential (eg, sterilized, postmenopausal).
• 3. Female participants 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.
• 4. 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

• 1. Systolic blood pressure greater than 185 mm Hg.
• 2. 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:
• 3. Is hypersensitive to AII receptor blockers.
• 4. 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.
• 5. History of moderate to severe heart failure or hypertensive encephalopathy.
• 6. Has clinically significant cardiac conduction defects (eg, third-degree atrioventricular block, sick sinus syndrome).
• 7. Has secondary hypertension of any etiology.
• 8. Known or suspected unilateral or bilateral renal artery stenosis.
• 9. Has severe renal dysfunction or disease (based on calculated creatinine clearance <
• 30 mL/min/1.73 m2) at Screening.

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 Investigator: Takeda Global Research & Development Center, Inc. Industry

Overall Clinical Trial Officials and Contacts

VP Clinical Science Strategy Study Director Takeda Global Research & Development Center, Inc.  

Information obtained from ClinicalTrials.gov on February 12, 2012

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

EDARBI Package Insert