A Study to Evaluate the Effectiveness and Safety of a Fixed Dose Combination of Azilsartan Medoxomil and Chlorthalidone in Patients With High Blood Pressure Who do Not Achieve Target Blood Pressure Following Treatment With Azilsartan Medoxomil Alone
Condition: Essential Hypertension
MeSH terms: Hypertension; Essential Hypertension
Intervention: Azilsartan medoxomil/placebo; Azilsartan medoxomil - chlorthalidone
Intervention description: Azilsartan medoxomil and placebo to chlorthalidone combination tablets; Azilsartan medoxomil and chlorthalidone fixed dose combination tablets
Intervention MeSH terms: Chlorthalidone; Azilsartan medoxomil
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 507.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: High Blood Pressure; Drug Therapy

Summary:

      The purpose of this study is to evaluate the efficacy and safety of the fixed dose
      combinations of azilsartan medoxomil plus chlorthalidone (40/12.5 and 40/25 mg), once daily,
      in participants with grades 2 or 3 essential hypertension who do not reach target blood
      pressure following treatment with 40 mg azilsartan medoxomil monotherapy after 4 weeks.
    

Eligibility criteria:

        Inclusion Criteria:

        At Screening

          1. The participant has grade 2-3 essential hypertension which is not adequately
             controlled, as defined by mean, trough, sitting, clinic systolic blood pressure (SBP):

               -  ≥160 to ≤180 mm Hg in participants who have not received any antihypertensive
                  medication in the 14 days prior to Visit 1.

               -  ≥150 to ≤170 mm Hg in participants taking 1 antihypertensive medication at Visit
                  1.

               -  ≥140 to ≤160 mm Hg in participants taking 2 antihypertensive medications at Visit
                  1.

          2. The participant has clinical laboratory test results (clinical chemistry, hematology,
             and complete urinalysis) within the reference range for the testing laboratory or the
             investigator does not consider the results to be clinically relevant for precluding
             entry in to the study in this hypertensive population.

          3. The participant is willing to discontinue current antihypertensive medications.

          4. In the opinion of the investigator, the participant is capable of understanding and
             complying with protocol requirements.

          5. 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.

          6. Male or female adult, at least 18 years of age.

          7. A female 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. 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).

             Post-placebo run-in:

          8. The participant must have a post-placebo run-in, 24-hour mean SBP by ambulatory blood
             pressure monitoring (ABPM) of 140-175 mm Hg inclusive, and a clinic SBP measurement of
             160 to 190 mm Hg inclusive (determined by the mean of 3 sitting, trough, measurements
             on Day -29) to qualify for entry in to the 4 week single-blind TAK-491 40 mg
             monotherapy treatment period.

             Post-4 week, single-blind TAK-491 40 mg monotherapy treatment:

          9. The participant does not achieve target blood pressure (defined as clinic SBP ≥140 mm
             Hg as determined by the mean of 3 sitting, trough, measurements) following 4 weeks
             single-blind treatment with TAK-491 40 mg monotherapy at Day -1, prior to
             randomization to double-blind treatment.

        Exclusion Criteria:

        At Screening

          1. The participant has clinic diastolic blood pressure (DBP) >110 mm Hg.

          2. The participant's 3 SBP measurements differ by more than 15 mm Hg (confirmed by a
             second set of three measurements).

          3. The participant has received any investigational compound within 30 days prior to
             Screening or is currently participating in another investigational study. NOTE:
             Participants participating in observational studies (per local definition) may enter
             Screening provided that the last intervention or invasive procedure was >30 days prior
             to Visit 1.

          4. The participant has been randomized/enrolled in a previous TAK-491 or TAK-491CLD
             study. NOTE: This criterion does not apply to participants who entered screening or
             placebo run-in in another TAK-491 or TAK-491CLD study but were not
             randomized/enrolled.

          5. The participant is a study site employee or is in a dependent relationship with a
             study site employee who is involved in conduct of this study (e.g., spouse, parent,
             child, sibling) or may consent under duress.

          6. The participant is currently treated with more than 2 antihypertensive medications.

          7. The participant works a night (third) shift (defined as 11 PM [2300] to 7 AM [0700]).

          8. The participant has an upper arm circumference <24 cm or >42 cm.

          9. The participant has secondary hypertension of any etiology (e.g., renovascular
             disease, pheochromocytoma, Cushing's syndrome).

         10. The participant has any history of myocardial infarction, heart failure, unstable
             angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive
             encephalopathy, cerebrovascular accident, persistent or permanent atrial fibrillation
             or transient ischemic attack.

         11. The participant has clinically significant cardiac conduction defects (e.g.,
             third-degree atrioventricular block, sick sinus syndrome).

         12. The participant has hemodynamically significant left ventricular outflow obstruction
             due to aortic valvular disease or hypertrophic cardiomyopathy.

         13. The participant has severe renal dysfunction or disease [based on estimated glomerular
             filtration rate (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).

         14. Participant has known hemodynamically significant bilateral renal artery stenosis or
             unilateral disease in a single kidney.

         15. The participant has a history of cancer that has not been in remission for at least 5
             years prior to the first dose of single-blind TAK-491 monotherapy study drug. (This
             criterion does not apply to those participants with basal cell or Stage 1 squamous
             cell carcinoma of the skin).

         16. The participant has poorly-controlled type 1 or 2 diabetes mellitus (hemoglobin A1c
             [HbA1c] >8.5%) at Screening.

         17. The participant has hypokalemia or hyperkalemia (defined as serum potassium outside of
             the normal reference range of the central laboratory) at Screening.

         18. The participant has an alanine aminotransferase or aspartate aminotransferase level
             >2.5 times the upper limit of normal, active liver disease, or jaundice at Screening.

         19. The participant 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.

         20. The participant has a history of hypersensitivity or allergies to angiotensin II
             receptor blockers (ARB) or thiazide-type diuretics or other sulfonamide-derived
             compounds.

         21. The participant has a history of drug abuse (defined as any illicit drug use) or a
             history of alcohol abuse per local guidelines within the past 2 years.

         22. The participant is required to take excluded medications at any point during the
             study.

         23. If female, the participant 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.

             Post-placebo run-in period

         24. The participant has a clinic SBP >190 mm Hg and DBP >115 mm Hg.

         25. The participant is noncompliant (<70% or >130%) with study medication during the
             placebo run-in period.

         26. The participant has a 24-hour mean eligibility ABPM reading of insufficient quality.

             Post-single-blind TAK-491 40 mg treatment period

         27. The participant has a clinic SBP >180 mm Hg and DBP >110 mm Hg.

         28. The participant is noncompliant (<70% or >130%) with study medication during the
             TAK-491 40 mg single-blind treatment period.