The purpose of this study is to evaluate the efficacy and safety of the fixed dose
combinations of azilsartan medoxomil plus chlorthalidone, once daily (QD), 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.
Change from baseline to Week 8 in Trough, Sitting, Clinic Diastolic Blood PressureChange from Baseline to Week 8 in Trough (22 to 24 hours after dosing) Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring
Change from Baseline to Week 8 in Trough Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring
Change From Baseline to Week 8 in the 24-hour Mean Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Change From Baseline to Week 8 in the 24-hour Mean Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Change From Baseline to Week 8 in the Mean Daytime (6 AM to 10 PM) Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Change From Baseline to Week 8 in the Mean Daytime (6 AM to 10 PM) Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Change From Baseline to Week 8 in the Mean Nighttime (12 AM to 6 AM) Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Change From Baseline to Week 8 in the Mean Nighttime (12 AM to 6 AM) Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Change From Baseline to Week 8 in the Mean Systolic Blood Pressure at 0 to 12 Hours After Dosing, as Measured by Ambulatory Blood Pressure Monitoring
Change From Baseline to Week 8 in the Mean Diastolic Blood Pressure at 0 to 12 Hours After Dosing, as Measured by Ambulatory Blood Pressure Monitoring
Percentage of Participants Who Achieve a Target Clinic Systolic Blood Pressure at Week 8, as Defined by Trough, sitting clinic Systolic Blood Pressure <140 mm Hg (or <130 mm Hg for patients with diabetes or chronic kidney disease)
Percentage of Participants Who Achieve a Target Clinic Diastolic Blood Pressure at Week 8, Defined as Trough, sitting, clinic Diastolic Blood Pressure <90 mm Hg (or <80 mm Hg for patients with diabetes or chronic kidney disease)
Percentage of Participants Who Achieve Both Clinic Systolic and Diastolic Blood Pressure Targets at Week 8
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. The participant is a man or woman and aged 18 years or older, inclusive.
7. 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. 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. 73m2 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
(as described in Appendix E).
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.
Takeda Study Registration Call Center, Phone: 800-778-2860, Email: medicalinformation@tpna.com
