• 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. ] [ Designated as safety issue: No ]
  The change in sitting clinic diastolic blood pressure measured at final visit or week 32 from Double-blind Baseline/Week 26. Diastolic blood pressure is the arithmetic mean of the 3 trough sitting diastolic blood pressure measurements. Each participant's blood pressure at the Final Visit/Week 26 of the open-label phase represented their Baseline blood pressure for the double-blind reversal phase.
  
  

• 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. ] [ Designated as safety issue: No ]
  The change in sitting clinic systolic blood pressure measured at final visit or week 32 from Double-blind Baseline/Week 26.. Systolic blood pressure is the arithmetic mean of the 3 trough sitting systolic blood pressure measurements. Each participant's blood pressure at the Final Visit/Week 26 of the open-label phase represented their Baseline blood pressure for the double-blind reversal phase.
  
  
• Change From Open Label Baseline (Week 0) in Sitting Clinic Diastolic Blood Pressure to Week 26 [ Time Frame: Baseline and Week 26. ] [ Designated as safety issue: No ]
  The change from baseline in sitting clinic diastolic blood pressure measured at final visit or week 26.
  
  
• Change From Open Label Baseline (Week 0) in Sitting Clinic Systolic Blood Pressure to Week 26 [ Time Frame: Baseline and Week 26. ] [ Designated as safety issue: No ]
  The change from baseline in sitting clinic systolic blood pressure measured at final visit or week 26.
  
  
• Number of Participants With Adverse Events During the Open-Label Phase [ Time Frame: Baseline to Week 26 ] [ Designated as safety issue: Yes ]
  Treatment-emergent adverse events defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 14 days after last dose of study drug, or within 30 days after the last dose of study drug for serious adverse event (SAE). A SAE is defined as any untoward medical occurrence that either results in death; is life-threatening; requires hospitalization; results in persistent or significant disability/incapacity; leads to a congenital anomaly/birth defect; or is an important medical event.
  
  
• Number of Participants With Adverse Events in the Double-Blind Baseline Phase [ Time Frame: Double-blind Baseline/Week 26 to Week 32 ] [ Designated as safety issue: Yes ]
  Treatment-emergent adverse events defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 14 days after last dose of study drug, or within 30 days after the last dose of study drug for SAE. A SAE is defined as any untoward medical occurrence that either results in death; is life-threatening; requires hospitalization; results in persistent or significant disability/incapacity; leads to a congenital anomaly/birth defect; or is an important medical event.
  
  

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.