The purpose of this study is to evaluate long term safety and tolerability of azilsartan medoxomil and chlorthalidone, once daily (QD), compared with olmesartan medoxomil and hydrochlorothiazide in hypertensive participants with moderate renal impairment.

A major component of blood pressure regulation is the renin-angiotensin-aldosterone system (RAAS). Drugs that modulate the RAAS are used commonly worldwide for the treatment of hypertension. TAK-491 (azilsartan medoxomil) is a prodrug of TAK-536 (azilsartan), an angiotensin II receptor blocker (ARB). Azilsartan medoxomil is being evaluated by Takeda to treat participants with essential hypertension.

Chlorthalidone is an orally administered thiazide-like diuretic agent, and long-term outcomes trials show blood pressure reductions associated with chlorthalidone treatment reduce risk of cardiovascular morbidity and mortality.

Hypertensive patients with moderate renal impairment are a relatively more severe and resistant hypertension population, and may benefit from effective fixed-dose combination treatments such as an ARB plus a diuretic for blood pressure control.

Participants will be randomized to receive azilsartan medoxomil and chlorthalidone or olmesartan medoxomil and hydrochlorothiazide for up to 52 weeks to evaluate long term safety of azilsartan medoxomil and chlorthalidone. A titration-to-target blood pressure approach will be used to guide the titration of study medication in this trial.

Inclusion Criteria:

1. Is treated with 2 or 3 antihypertensive medications and on stable therapy, defined as ≥6 weeks on medication, and has a mean sitting clinic systolic blood pressure ≥135 and ≤160 mm Hg at the Screening Visit and on Day 1.
2. Has an estimated glomerular filtration rate (eGFR) in the range of ≥30 to <60 mL/min/1.73 m^2 (Stage 3 chronic kidney disease) at the Screening Visit.
3. Is a man or woman and aged 18 years or older.
4. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of the informed consent through 30 days after the last study drug dose.
5. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
6. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
7. Has clinical laboratory test results (clinical chemistry, hematology, and complete urinalysis) that the investigator does not consider to be clinically significant in this moderate renal impaired population.
8. Is willing to discontinue the current antihypertensive medications 2 days prior to randomization.

Exclusion Criteria:

1. Has received any investigational compound within 30 days prior to Screening or is currently participating in another investigational study.
2. Has been randomized/enrolled in a previous TAK-491 or TAK-491CLD study. NOTE: This criterion does not apply to participants who began participation in another TAK-491 or TAK-491CLD study but were not randomized/enrolled, nor does it apply to participants who participated in observational studies that lacked an intervention or invasive procedure.
3. Is receiving a combination of olmesartan and hydrochlorothiazide at the Screening Visit.
4. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
5. Has a mean clinic diastolic (sitting, trough) >110 mm Hg on Day 1.
6. Has secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome).
7. Has a recent history (within the last 6 months) of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.
8. Has clinically significant cardiac conduction defects (ie, third-degree atrioventricular block, sick sinus syndrome).
9. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
10. Has severe renal dysfunction or disease (based on eGFR <30 mL/min/1.73m^2 at Screening) prior renal transplantation or nephrotic syndrome (defined as a urinary albumin/creatinine ratio >2000 mg/g at Screening).
11. Has known or suspected unilateral or bilateral renal artery stenosis.
12. Has a 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 participants with basal cell or stage I squamous cell carcinoma of the skin.)
13. Has poorly-controlled type 1 or 2 diabetes mellitus (glycosylated hemoglobin A [HbA1c] >8.5%) at Screening.
14. Has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory).
15. Has an alanine aminotransferase or aspartate aminotransferase level of >2.5 times the upper limit of normal, active liver disease, or jaundice.
16. Has any other known serious disease or condition that would compromise safety, might affect life expectancy, or make it difficult to successfully manage and follow the participant according to the protocol.
17. has a history of hypersensitivity or allergies to ARBs or thiazide-type diuretics or other sulfonamide-derived compounds.
18. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within the past 2 years.
19. Is required to take excluded medications.
20. If female, is pregnant or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.