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(s) targeted: Essential Hypertension

Intervention: Azilsartan medoxomil/placebo (Drug); Azilsartan medoxomil - chlorthalidone (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Takeda

Official(s) and/or principal investigator(s):
Medical Director, Clinical Science, Study Director, Affiliation: Takeda

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.

Official title: A Phase-3 Randomized, Double-Blind, Efficacy and Safety Study Evaluating the Fixed Dose Combinations of TAK-491 Plus Chlorthalidone (40/12.5 mg and 40/25 mg) in Subjects With Grades 2 or 3 Essential Hypertension, Who Do Not Achieve Target Blood Pressure Following Treatment With TAK-491 40 mg Monotherapy

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure

Secondary outcome:

Change From Baseline to Week 8 in Trough, Sitting, Clinic Diastolic Blood Pressure

Change From Baseline to Week 8 in Trough 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 Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

Change From Baseline to Week 8 in the Mean Daytime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

Change From Baseline to Week 8 in the Mean Nighttime Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

Change From Baseline to Week 8 in the Mean Nighttime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

Change From Baseline to Week 8 in the Mean Systolic Blood Pressure 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 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

Percentage of Participants Who Achieve a Target Clinic Diastolic Blood Pressure at Week 8

Percentage of Participants Who Achieve Both Clinic Systolic and Diastolic Blood Pressure Targets at Week 8

Detailed description:

Eligible participants completed a 2-week single-blind run-in period (Days - 42 to -29) prior

to a Single-Blind Monotherapy Treatment Period (Day - 28 to Day -1) where they received

azilsartan medoxomil 40 mg. After the Single-Blind Monotherapy Treatment Period, those participants who achieved target blood pressure discontinued treatment and resumed standard of care management at the discretion of their treating physician, while those participants who did not achieve target blood pressure (defined as clinic systolic blood pressure ≥140 mmHg) were randomly assigned to 1 of 3 active treatment arms: azilsartan medoxomil 40 mg plus placebo, azilsartan medoxomil plus chlorthalidone 40/12. 5 mg, or azilsartan medoxomil plus chlorthalidone 40/25 mg.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Haskovo, Bulgaria

Pazardzhik, Bulgaria

Pleven, Bulgaria

Plovdiv, Bulgaria

Sofia, Bulgaria

Varna, Bulgaria

Veliko Tarnovo, Bulgaria

Paide, Estonia

Saku, Estonia

Tallinn, Estonia

Tartu, Estonia

Voru, Estonia

Hamburg, Germany

Budapest, Hungary

Debrecen, Hungary

Gyongyos, Hungary

Gyula, Hungary

Mosonmagyarovar, Hungary

Nyiregyhaza, Hungary

Pecs, Hungary

Szikszo, Hungary

Bologna, Italy

Brescia, Italy

Ferrara, Italy

L'Aquila, Italy

Milano, Italy

Palermo, Italy

Pavia, Italy

Pisa, Italy

Roma, Italy

Sassari, Italy

Alytus, Lithuania

Kaunas, Lithuania

Beek, Netherlands

Breda, Netherlands

Eindhoven, Netherlands

Groningen, Netherlands

Leiderdorp, Netherlands

Maastricht, Netherlands

Rotterdam, Netherlands

Velp, Netherlands

Zoetermeer, Netherlands

Zwijndrecht, Netherlands

Bydgoszcz, Poland

Gdansk, Poland

Gdynia, Poland

Krakow, Poland

Lodz, Poland

Lublin, Poland

Oswiecim, Poland

Parczew, Poland

Poznan, Poland

Pulway, Poland

Rzeszow, Poland

Sopot, Poland

Torun, Poland

Zgierz, Poland

Belgrade, Serbia

Kragujevac, Serbia

Krusevac, Serbia

Nis, Serbia

Sremska Kamenica, Serbia

Zemun, Serbia

Bardejov, Slovakia

Bratislava, Slovakia

Galanta, Slovakia

Komarno, Slovakia

Kosice, Slovakia

Lucenec, Slovakia

Martin, Slovakia

Nitra, Slovakia

Nove Zamky, Slovakia

Presov, Slovakia

Svidnik, Slovakia

Zilina, Slovakia

Barcelona, Spain

Madrid, Spain

Malaga, Spain

Goteborg, Sweden

Lund, Sweden

Malmo, Sweden

Vallingby, Sweden

Torrette di Ancona, Ancona, Italy

Karlsruhe, Baden Wuerttemberg, Germany

Centelles, Barcelona, Spain

Acquaviva delle Fonti, Bari, Italy

Bad Woerishofen, Bayern, Germany

Nuernberg, Bayern, Germany

London, Greater London, United Kingdom

Labarthe Sur Leze, Haute Garonne, France

Frankfurt, Hessen, Germany

Bourg-des-Comptes, Ille et Vilaine, France

Tours, Indre et Loire, France

Vourey, Isere, France

Glasgow, Lanarkshire, United Kingdom

Blackpool, Lancashire, United Kingdom

Saint Etienne, Loire, France

Northwood, Middlesex, United Kingdom

Stuhr, Niedersachsen, Germany

Essen, Nordrhein Westfalen, Germany

Kamp-Lintfort, Nordrhein Westfalen, Germany

Orthez, Pyrenees Atlantiques, France

Mainz, Rheinland Pfalz, Germany

Dresden, Sachsen, Germany

Bath, Somerset, United Kingdom

Legnago, Verona, Italy

Leamington Spa, Warwickshire, United Kingdom

Westbury, Wiltshire, United Kingdom

FDA Safety Alerts and Recalls

EDARBYCLOR Package Insert

Starting date: October 2011
Last updated: March 21, 2014