Efficacy and Safety of Azilsartan Medoxomil Combined With Chlorthalidone in Participants With Moderate to Severe Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy and safety of azilsartan medoxomil combined with chlorthalidone, once daily (QD), in participants with moderate to severe hypertension.

Detailed Description
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According to the World Health Organization (WHO), hypertension is the most common attributable cause of preventable death in developed nations, as uncontrolled hypertension greatly increases the risk of cardiovascular disease, cerebrovascular disease, and renal failure. As the population ages, the prevalence of hypertension will continue to increase if broad and effective preventive measures are not implemented. Despite the availability of antihypertensive agents, hypertension remains inadequately controlled; only about one third of patients continue to maintain control successfully. Although most antihypertensive agents are effective at the appropriate dose, the majority have side effects that limit their use. As a class, angiotensin II receptor blockers generally are considered more tolerable than other classes of antihypertensive agents. TAK-491 (azilsartan medoxomil) is an angiotensin II receptor blocker that is being evaluated by Takeda to treat essential hypertension. Treatments for essential hypertension commonly include use of a thiazide-like diuretic, either alone or as part of combination treatment. This study is designed to compare the antihypertensive effect and the safety and tolerability of the azilsartan medoxomil plus chlorthalidone fixed-dose combination product (TAK 491CLD FDC) with azilsartan monotherapy and chlorthalidone monotherapy during 8 weeks of treatment. Participants in this study will be randomized to receive one of 11 possible dosing combinations of azilsartan medoxomil , chlorthalidone and placebo over an 8 week period. The total duration of the study will be approximately 13 weeks. Participants will make 12 visits to the clinic. Each participant will also be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

Official Title
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A Phase 3, Double-Blind, Randomized, Factorial, Efficacy and Safety Study of TAK 491 Plus Chlorthalidone Fixed-Dose Combination in Participants With Moderate to Severe Hypertension

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Azilsartan medoxomil and chlorthalidone
* Drug: Azilsartan medoxomil and chlorthalidone
* Drug: Azilsartan medoxomil and chlorthalidone
* Drug: Azilsartan medoxomil and chlorthalidone
* Drug: Azilsartan medoxomil and chlorthalidone
* Drug: Azilsartan medoxomil and chlorthalidone
* Drug: Chlorthalidone
* Drug: Chlorthalidone
* Drug: Azilsartan medoxomil
* Drug: Azilsartan medoxomil
* Drug: Azilsartan medoxomil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is treated with antihypertensive therapy and has a post-washout mean sitting clinic systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm Hg on the day prior to randomization, or the participant has not received antihypertensive treatment within 28 days prior to Screening and has a mean sitting clinic systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm Hg at the Screening Visit and on the day prior to randomization. Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study. Has clinical laboratory test results within the reference range for the testing laboratory or the investigator does not consider the results to be clinically significant. Is willing to discontinue current antihypertensive medications on Day -21 or on Day -28 if on amlodipine or chlorthalidone. Exclusion Criteria: Has a mean sitting clinic diastolic blood pressure greater than 119 mm Hg on the day prior to randomization. Has a baseline 24-hour ambulatory blood pressure measurement reading of insufficient quality. Has works a night (third) shift (defined as 11 PM [2300] to 7 AM [0700]). Has an upper arm circumference less than 24 cm or greater than 42 cm. Has is noncompliant with study medication during the placebo run-in period. Has secondary hypertension of any etiology. Has recent history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack. Has clinically significant cardiac conduction defects. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease. Has severe renal dysfunction or disease. Has known or suspected unilateral or bilateral renal artery stenosis. Has a history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug. Has poorly controlled type 1 or type 2 diabetes mellitus at Screening. Has hypokalemia or hyperkalemia. Has an alanine aminotransferase or aspartate aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice. 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 Has according to the protocol. Has known hypersensitivity to angiotensin II receptor blockers, thiazide-type diuretics or other sulfonamide-derived compounds. Has been randomized in a previous azilsartan medoxomil study. Is currently participating in another investigational study or is receiving or has received any investigational compound within 30 days prior to Screening. Has a history of drug abuse or a history of alcohol abuse within the past 2 years.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azilsartan medoxomil 20 mg/chlorthalidone 12.5 mg QD<br> | Drug: Azilsartan medoxomil and chlorthalidone<br>* Azilsartan medoxomil 20 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily for up to 8 weeks<br>* Other names: TAK-491CLD;|
| Experimental: Azilsartan medoxomil 20 mg/chlorthalidone 25 mg QD<br> | Drug: Azilsartan medoxomil and chlorthalidone<br>* Azilsartan medoxomil 20 mg and chlorthalidone 25 mg combination tablets, orally, once daily for up to 8 weeks<br>* Other names: TAK-491CLD;|
| Experimental: Azilsartan medoxomil 40 mg/chlorthalidone 12.5 mg QD<br> | Drug: Azilsartan medoxomil and chlorthalidone<br>* Azilsartan 40 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily for up to 8 weeks<br>* Other names: TAK-491CLD;|
| Experimental: Azilsartan medoxomil 40 mg/chlorthalidone 25 mg QD<br> | Drug: Azilsartan medoxomil and chlorthalidone<br>* Azilsartan medoxomil 40 mg and chlorthalidone 25 mg combination tablets, orally, once daily for up to 8 weeks<br>* Other names: TAK-491CLD;|
| Experimental: Azilsartan medoxomil 80 mg/chlorthalidone 12.5 mg QD<br> | Drug: Azilsartan medoxomil and chlorthalidone<br>* Azilsartan 80 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily for up to 8 weeks<br>* Other names: TAK-491CLD;|
| Experimental: Azilsartan medoxomil 80 mg/chlorthalidone 25 mg QD<br> | Drug: Azilsartan medoxomil and chlorthalidone<br>* Azilsartan medoxomil 80 mg and chlorthalidone 25 mg combination tablets, orally, once daily for up to 8 weeks<br>* Other names: TAK-491CLD;|
| Active Comparator: Chlorthalidone 12.5 mg QD<br> | Drug: Chlorthalidone<br>* Azilsartan medoxomil placebo and chlorthalidone 12.5 mg combination tablets, orally, once daily for up to 8 weeks<br>|
| Active Comparator: Chlorthalidone 25 mg QD<br> | Drug: Chlorthalidone<br>* Azilsartan medoxomil placebo and chlorthalidone 25 mg combination tablets, orally, once daily for up to 8 weeks<br>|
| Experimental: Azilsartan medoxomil 20 mg QD<br> | Drug: Azilsartan medoxomil<br>* Azilsartan medoxomil 20 mg and chlorthalidone placebo combination tablets, orally, once daily for up to 8 weeks<br>* Other names: TAK-491CLD;|
| Experimental: Azilsartan medoxomil 40 mg QD<br> | Drug: Azilsartan medoxomil<br>* Azilsartan medoxomil 40 mg and chlorthalidone placebo combination tablets, orally, once daily for up to 8 weeks<br>* Other names: TAK-491CLD;|
| Experimental: Azilsartan medoxomil 80 mg QD<br> | Drug: Azilsartan medoxomil<br>* Azilsartan medoxomil 80 mg and chlorthalidone placebo combination tablets, orally, once daily for up to 8 weeks<br>* Other names: TAK-491CLD;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 8 in Trough, Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring (Pooled Analysis) | The change in trough systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The trough is the average of all measurements recorded from 22 to 24 hours after dosing. | Baseline and Week 8. | 
| Change From Baseline to Week 8 in Trough, Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring (Pairwise Analysis) | The change in trough systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The trough is the average of all measurements recorded from 22 to 24 hours after dosing. | Baseline and Week 8. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure | The change in trough systolic blood pressure measured at final visit or week 8 relative to baseline. Systolic blood pressure is the arithmetic mean of the 3 serial trough sitting systolic blood pressure measurements. | Baseline and Week 8 | 
| Change From Baseline to Week 8 in Trough Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring in Black Participants (Pooled Analysis) | The change in trough systolic blood pressure in black subjects measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The trough is the average of all measurements recorded from 22 to 24 hours after dosing. | Baseline and Week 8. | 
| Change From Baseline to Week 8 in Trough Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring in Black Participants (Pairwise Analysis) | The change in trough systolic blood pressure in black participants as measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The trough is the average of all measurements recorded from 22 to 24 hours after dosing. | Baseline and Week 8. | 
| Change From Baseline to Week 8 in Trough, Sitting, Clinic Diastolic Blood Pressure | The change in trough diastolic blood pressure measured at final visit or week 8 relative to baseline. Diastolic blood pressure is the average of the 3 serial trough clinic sitting diastolic blood pressure measurements. | Baseline and Week 8. | 
| Change From Baseline to Week 8 in the Mean Trough Diastolic Blood Pressure (22 to 24 Hours After Dosing), as Measured by Ambulatory Blood Pressure Monitoring. | The change in trough diastolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The trough is the average of all measurements recorded from 22 to 24 hours after dosing. | Baseline and Week 8. | 
| Change From Baseline to Week 8 in the 24-hour Mean Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring | The change in 24-hour mean systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 24-hour mean is the average of all measurements recorded for 24 hours after dosing. | Baseline and Week 8. | 
| Change From Baseline to Week 8 in the 24-hour Mean Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring | The change in 24-hour mean diastolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 24-hour mean is the average of all measurements recorded for 24 hours after dosing. | Baseline and Week 8. | 
| 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. | The change in daytime (6am to 10pm) mean systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Daytime mean is the average of all measurements recorded between the hours of 6 am and 10 pm. | Baseline and Week 8. | 
| 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. | The change in daytime (6am to 10pm) mean diastolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Daytime mean is the average of all measurements recorded between the hours of 6 am and 10 pm. | Baseline and Week 8. | 
| 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. | The change in nighttime (12am to 6am) mean systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Nighttime mean is the average of all measurements recorded between the hours of 12 am and 6 am. | Baseline and Week 8. | 
| 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. | The change in nighttime (12am to 6am) mean diastolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Nighttime mean is the average of all measurements recorded between the hours of 12 am and 6 am. | Baseline and Week 8. | 
| 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. | The change in the 12-hour mean systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 12-hour mean is the average of all measurements recorded in the first 12 hours after dosing. | Baseline and Week 8 | 
| 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. | The change in the 12-hour mean diastolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 12-hour mean is the average of all measurements recorded in the first 12 hours after dosing. | Baseline and Week 8. | 
| Percentage of Participants Who Achieve a Clinic Systolic Blood Pressure Response at Week 8, as Defined by Clinic Systolic Blood Pressure <140 mm Hg and/or a Reduction of ≥20 mm Hg From Baseline. | Percentage of participants who achieve a clinic systolic blood pressure response measured at week 8, defined as less than 140 mm Hg and/or reduction from baseline of greater than or equal to 20 mm Hg. Systolic blood pressure is the average of the 3 serial trough sitting clinic systolic blood pressure measurements. | Baseline and Week 8 | 
| Percentage of Participants Who Achieve a Clinic Diastolic Blood Pressure Response at Week 8, Defined as Clinic Diastolic Blood Pressure <90 mm Hg and/or a Reduction of ≥10 mm Hg From Baseline. | Percentage of participants who achieve a clinic diastolic blood pressure response measured at week 8, defined as less than 90 mm Hg and/or reduction from baseline of greater than or equal to 10 mm Hg. Diastolic blood pressure is the average of the 3 serial trough sitting clinic diastolic blood pressure measurements. | Baseline and Week 8. | 
| Percentage of Participants Who Achieve Both a Clinic Systolic and Diastolic Blood Pressure Response at Week 8. | Percentage of participants who achieve both a clinic systolic and diastolic blood pressure response measured at week 8, defined as systolic blood pressure less than 140 mm Hg and/or reduction from baseline of greater than or equal to 20 mm Hg AND diastolic blood pressure less than 90 mm Hg and/or reduction from baseline of greater than or equal to 10 mm Hg . Systolic/diastolic blood pressure is based on the average of the 3 serial trough clinic sitting systolic/diastolic blood pressure measurements. | Baseline and Week 8. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertensive, Blood Pressure, High, Vascular Disease, Cardiovascular Disease, Drug Therapy