A Randomized, Open-Label, Phase 3 Study to Compare Long-Term Safety and Tolerability of
the TAK-491 and Chlorthalidone Fixed-Dose Combination Versus Olmesartan Medoxomil and
Hydrochlorothiazide Fixed-Dose Combination in Hypertensive Subjects With Moderate Renal
Impairment

1. The subject is treated with 2 or 3 antihypertensive medications and on stable therapy, defined as >6 weeks on medication, and has a mean sitting clinic SBP >=135 and <=160 mmHg at the Screening Visit and on Day 1.
2. The subject has estimated glomerular filtration rate (eGFR) in the range of >=30 to <60 ml/min/1.73 m2 [Stage 3 chronic kidney disease (CKD)] at the Screening visit.
3. The subject is a man or woman and aged 18 years or older.
4. A female subject of childbearing potential who is sexually active with a male partner agrees to routinely use adequate contraception from signing of the informed consent through 30 days after the last study drug dose.
NOTE: Women NOT of childbearing potential are defined as those who have been surgically sterilized (hysterectomy, bilateral oophorectomy, tubal ligation [performed more than one 1 year prior to Screening]) or who are postmenopausal (defined as at least 1 year since last regular menses).
5. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
6. The subject or, when applicable, the subject*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. The subject 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. The subject is willing to discontinue the current antihypertensive medications 2 days prior to randomization.

1. The subject has received any investigational compound within 30 days prior to Screening or is currently participating in another investigational study.
2. The subject has been randomized/enrolled in a previous TAK-491 or TAK-491CLD study.
NOTE: This criterion does not apply to subjects who began participation in another TAK 491 or TAK-491CLD study but were not randomized/enrolled, nor does it apply to subjects who participated in observational studies that lacked an intervention or invasive procedure.
3. The subject receives a combination of OLM and HCTZ at the Screening visit.
4. The subject 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. The subject has a mean clinic DBP (sitting, trough) >110 mmHg on Day 1.
6. The subject has secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing*s syndrome).
7. The subject 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. The subject has clinically significant cardiac conduction defects (ie, third-degree atrioventricular block, sick sinus syndrome).
9. The subject has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
10. The subject has severe renal dysfunction or disease [based on eGFR <30 mL/min/1.73m2 at screening] or nephrotic syndrome [defined as a urinary albumin/creatinine ratio >2000 mg/g at screening].
11. Subject has known or suspected unilateral or bilateral renal artery stenosis.
12. The subject 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 subjects with basal cell or Stage 1 squamous cell carcinoma of the skin).
13. The subject has poorly-controlled type 1 or 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8.5%) at Screening.
14. The subject has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory).
15. The subject has an alanine aminotransferase or aspartate aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.
16. The subject 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 subject according to the protocol.
17. The subject has a history of hypersensitivity or allergies to ARBs or thiazide-type diuretics or other sulfonamide-derived compounds.
18. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within the past 2 years.
19. The subject is required to take excluded medications (see Section 7.3 Excluded Medications and Treatments).
20. If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.