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

A Phase 3, Double-Blind, Randomized, Efficacy and Safety Study Comparing the TAK-491 Plus Chlorthalidone Fixed-Dose Combination vs Benicar HCT® (Olmesartan Medoxomil-Hydrochlorothiazide) in Subjects With Moderate to Severe Essential Hypertension

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00846365

Enrollment

1085

Registered

2009-02-18

Start date

2009-03-31

Completion date

2010-06-30

Last updated

2012-03-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Essential Hypertension

Keywords

Essential Hypertension, Hypertensive, Blood Pressure, High, Vascular Disease, Cardiovascular Disease, Drug Therapy

Brief summary

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 essential hypertension.

Detailed description

According to the World Health Organization, 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 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. Although chlorthalidone was commonly prescribed in the past, its use has widely been replaced with hydrochlorothiazide, presumably due to a lack of available combination products containing chlorthalidone, the assumption that hydrochlorothiazide and chlorthalidone have similar antihypertensive effects and cardiovascular benefits, and the perception that chlorthalidone use is associated with a greater frequency of hypokalemia. However, the frequency of hypokalemia with chlorthalidone use is relatively low in the dose range of 12.5 to 25 mg and these doses have been shown to be associated with potent blood pressure reduction. Several long-term outcomes trials have shown that blood pressure reductions associated with chlorthalidone treatment reduce risk of cardiovascular morbidity and mortality. Most hypertensive patients require two or more agents to achieve target blood pressure and diuretics are commonly used in combination with other antihypertensive agents. Participants in this study will be randomized to receive one of 3 possible dosing combinations of azilsartan medoxomil with either chlorthalidone or olmesartan medoxomil-hydrochlorothiazide over 8 weeks. The total duration of the study is approximately 13 weeks. Participants will make a total of 11 visits to the clinic, and will be required to participate in a follow-up telephone call 14 days after last dose of the study drug for adverse event assessment.

Interventions

DRUGAzilsartan medoxomil and chlorthalidone

Azilsartan medoxomil 20 mg and chlorthalidone 12.5 mg, tablets, orally, and olmesartan medoxomil-hydrochlorothiazide placebo tablets once daily for 8 weeks. If participant does not achieve target blood pressure at Week 4, then the dosage will be increased to azilsartan medoxomil 40 mg and chlorthalidone 25 mg, tablets, orally, once daily for the remaining 4 weeks.

DRUGOlmesartan medoxomil-hydrochlorothiazide

Olmesartan medoxomil 20 mg/hydrochlorothiazide 12.5 mg, tablets, orally, and Azilsartan medoxomil and chlorthalidone placebo-matching tablets, orally, once daily for 8 weeks. If participant does not achieve target blood pressure at Week 4, then the dosage will be increased to olmesartan medoxomil 40 mg/hydrochlorothiazide 25 mg, tablets, orally, once daily for the remaining 4 weeks.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. 190 mm Hg on Day -1 or if the participant has not received antihypertensive treatment within 28 days before 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 Day -1. 2. 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. 3. 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. 4. Is willing to discontinue current antihypertensive medications on Day -21 or on Day -28 if is on amlodipine or chlorthalidone.

Exclusion criteria

1. Has a mean sitting clinic diastolic blood pressure greater than 119 mm Hg. 2. Has a baseline 24-hour ambulatory blood pressure monitoring reading of insufficient quality. 3. Works a night (third) shift (from 11 PM \[2300\] to 7 AM \[0700\]). 4. Has an upper arm circumference less than 24 cm or greater than 42 cm. 5. Is noncompliant with study medication during the placebo run-in period. 6. Has secondary hypertension of any etiology. 7. Has a recent history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident or transient ischemic attack. 8. Has a clinically significant cardiac conduction. 9. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease. 10. Has severe renal dysfunction or disease. 11. Has a known or suspected unilateral or bilateral renal artery stenosis. 12. Has a history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug. 13. Has poorly controlled type 1 or type 2 diabetes mellitus. 14. Has hypokalemia or hyperkalemia. 15. 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. 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. 17. Has a known hypersensitivity to angiotensin II receptor blockers or thiazide-type diuretics or other sulfonamide-derived compounds. 18. Has been randomized in a previous Azilsartan Medoxomil study. 19. Is currently participating in another investigational study or has participated in an investigational study or is receiving or has received any investigational compound within 30 days prior to Randomization. 20. Has a history of drug abuse or a history of alcohol abuse within the past 2 years.

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure.	Baseline and Week 8.	The change in trough systolic blood pressure measured at week 8 or final visit relative to baseline. Systolic blood pressure is the average of the 3 serial trough sitting systolic blood pressure measurements.

Secondary

Measure	Time frame	Description
Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure	Baseline, Week 4 and Week 8.	The change in trough diastolic blood pressure measured at week 4 and week 8 relative to baseline. Diastolic blood pressure is the average of the 3 serial trough sitting diastolic blood pressure measurements.
Change From Baseline in Trough Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.	Baseline, Week 4 and Week 8.	The change in trough systolic blood pressure measured at week 4 and week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Trough is the average of all measurements recorded from 22 to 24 hours after dosing.
Change From Baseline in Trough Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.	Baseline, Week 4 and Week 8.	The change in trough systolic blood pressure measured at week 4 and week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Trough is the average of all measurements recorded from 22 to 24 hours after dosing.
Change From Baseline in 24-hour Mean Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.	Baseline, Week 4 and Week 8.	The change in the 24-hour mean systolic blood pressure at week4 and 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.
Change From Baseline in 24-hour Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.	Baseline, Week 4 and Week 8.	The change in the 0 to 24-hours-after-dosing mean diastolic blood pressure measured at Week 4 and Week 8 relative to baseline. . Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The mean consists of the average of measurements collected over the subsequent 24 hours.
Change From Baseline in Daytime Mean (6am to 10pm) Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.	Baseline, Week 4 and Week 8.	The change in the daytime, while awake (6am to 10pm) mean systolic blood pressure measured at Week 4 and 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 measurements recorded between the hours of 6 AM (inclusive) and 10 PM (exclusive) included in the 24-hour mean calculations.
Change From Baseline in Daytime Mean (6am to 10pm) Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.	Baseline, Week 4 and Week 8.	The change in the daytime, while awake (6am to 10pm) mean diastolic blood pressure measured at Week 4 and Week 8relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Daytime mean is the average of measurements recorded between the hours of 6 AM (inclusive) and 10 PM (exclusive) included in the 24-hour mean calculations.
Change From Baseline to Week 4 in Trough, Sitting, Clinic Systolic Blood Pressure.	Baseline and Week 4.	The change in trough systolic blood pressure measured at week 4 relative to baseline. Systolic blood pressure is the average of the 3 serial trough sitting systolic blood pressure measurements.
Change From Baseline in Nighttime Mean (12am to 6am) Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.	Baseline, Week 4 and Week 8.	The change in the nighttime, while asleep (12am to 6am) mean diastolic blood pressure measured at Week 4 and 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 (arithmetic mean) of measurements recorded between the hours of 12 AM (inclusive) and 6 AM (exclusive) included in the 24-hour mean calculations.
Change From Baseline in 12-hr Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.	Baseline, Week 4 and Week 8.	The change in the 0 to 12 hours-after-dosing mean Systolic Blood Pressure measured at Week 4 and Week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night The mean consists of the average (arithmetic mean) of measurements collected at each time frame and includes all observations recorded over the subsequent 12 hours.
Change From Baseline in 12-hr Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.	Baseline, Week 4 and Week 8.	The change in the 0 to 12 hours-after-dosing mean diastolic blood pressure measured at Week 4 and Week 8 to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The mean consists of the average (arithmetic mean) of measurements collected at each time frame and includes all observations recorded over the subsequent 12 hours.
Percentage of Participants Who Achieve a Clinic Systolic Blood Pressure Response, Defined as <140 mm Hg for Participants Without Diabetes or CKD or <130 mm Hg for Participants With Diabetes or CKD	Baseline, Week 2, Week 4, Week 6 and Week 8.	Percentage of participants who achieve a clinic systolic blood pressure response, defined as \<140 mm Hg for participants without diabetes or CKD or \<130 mm Hg for participants with diabetes or CKD at each time frame relative to baseline.
Percentage of Participants Who Achieve a Clinic Diastolic Blood Pressure Response, Defined as Defined as <90 mm Hg for Participants Without Diabetes or CKD or <80 mm Hg for Participants With Diabetes or CKD	Baseline, Week 2, Week 4, Week 6 and Week 8.	Percentage of participants who achieve a clinic diastolic blood pressure response, defined as defined as \<90 mm Hg for participants without diabetes or CKD or \<80 mm Hg for participants with diabetes or CKD at each time frame relative to baseline.
Percentage of Participants Who Achieve a Clinic Diastolic AND Systolic Blood Pressure Response, Defined as <140/90 mm Hg for Participants Without Diabetes or Chronic Kidney Disease (CKD) or <130/80 mm Hg for Participants With Diabetes or CKD	Baseline, Week 2, Week 4, Week 6 and Week 8.	Percentage of participants who achieve both a clinic diastolic blood pressure response, defined as \<140/90 mm Hg for participants without diabetes or chronic kidney disease (CKD) or \<130/80 mm Hg for participants with diabetes or CKD at each time frame relative to baseline.
Change From Baseline in Nighttime Mean (12am to 6am) Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring	Baseline, Week 4 and Week 8.	The change in the nighttime, while asleep (12am to 6am) mean systolic blood pressure measured at Week 4 and Week 8 to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Nighttime mean is the average of measurements recorded between the hours of 12 AM (inclusive) and 6 AM (exclusive) included in the 24-hour mean calculations.

Countries

Chile, Mexico, United States

Participant flow

Recruitment details

Participants enrolled at 93 investigative sites in Argentina, Chile, Mexico and the United States from 13 March 2009 to 25 June 2010.

Pre-assignment details

Participants with moderate to severe essential hypertension were enrolled in one of 3, once-daily (QD) treatment groups.

Participants by arm

Arm	Count
Azilsartan Medoxomil 20-40mg Plus Chlorthalidone 12.5-25 mg QD Azilsartan medoxomil 20 mg and chlorthalidone 12.5 mg, tablets, orally, and olmesartan medoxomil-hydrochlorothiazide placebo tablets once daily for 8 weeks. If participant does not achieve target blood pressure at Week 4, then the dosage will be increased to azilsartan medoxomil 40 mg and chlorthalidone 25 mg, tablets, orally, once daily for the remaining 4 weeks.	372
Azilsartan Medoxomil 40-80mg Plus Chlorthalidone 12.5-25 mg QD Azilsartan medoxomil 40 mg and chlorthalidone 12.5, mg, tablets, orally, and olmesartan medoxomil-hydrochlorothiazide placebo tablets once daily for 8 weeks. If participant does not achieve target blood pressure at Week 4, then the dosage will be increased to azilsartan medoxomil 80 mg and chlorthalidone 25 mg, tablets, orally, once daily for the remaining 4 weeks.	357
Olmesartan Medoxomil 20-40mg/Hydrochlorothiazide 12.5-25mg QD Olmesartan medoxomil 20 mg/hydrochlorothiazide 12.5 mg, tablets, orally, and Azilsartan medoxomil and chlorthalidone placebo-matching tablets, orally, once daily for 8 weeks. If participant does not achieve target blood pressure at Week 4, then the dosage will be increased to olmesartan medoxomil 40 mg/hydrochlorothiazide 25 mg, tablets, orally, once daily for the remaining 4 weeks.	356
Total	1,085

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	20	30	11
Overall Study	Lack of Efficacy	1	1	2
Overall Study	Lost to Follow-up	8	2	5
Overall Study	Other	9	1	6
Overall Study	Pregnancy	1	0	0
Overall Study	Protocol Violation	5	4	0
Overall Study	Withdrawal by Subject	11	11	9

Baseline characteristics

Characteristic	Azilsartan Medoxomil 20-40mg Plus Chlorthalidone 12.5-25 mg QD	Azilsartan Medoxomil 40-80mg Plus Chlorthalidone 12.5-25 mg QD	Olmesartan Medoxomil 20-40mg/Hydrochlorothiazide 12.5-25mg QD	Total
Age Continuous	55.5 years STANDARD_DEVIATION 10.49	56.7 years STANDARD_DEVIATION 10.83	55.7 years STANDARD_DEVIATION 9.78	56.0 years STANDARD_DEVIATION 10.38
Age, Customized 45 to 64 years	252 participants	244 participants	249 participants	745 participants
Age, Customized <45 years	47 participants	38 participants	41 participants	126 participants
Age, Customized ≥65 years	73 participants	75 participants	66 participants	214 participants
Body Mass Index (BMI)	31.7 kg/m^2 STANDARD_DEVIATION 5.94	31.8 kg/m^2 STANDARD_DEVIATION 6.4	31.9 kg/m^2 STANDARD_DEVIATION 6.08	31.8 kg/m^2 STANDARD_DEVIATION 6.14
Chronic Kidney Disease (CKD) Status Missing	0 participants	1 participants	0 participants	1 participants
Chronic Kidney Disease (CKD) Status No	347 participants	315 participants	328 participants	990 participants
Chronic Kidney Disease (CKD) Status Yes	25 participants	41 participants	28 participants	94 participants
Diabetes Status No	314 participants	298 participants	285 participants	897 participants
Diabetes Status Yes	58 participants	59 participants	71 participants	188 participants
Estimated Glomerular Filtration Rate (eGFR) Category Mild impairment	220 participants	207 participants	205 participants	632 participants
Estimated Glomerular Filtration Rate (eGFR) Category Moderate impairment	26 participants	25 participants	25 participants	76 participants
Estimated Glomerular Filtration Rate (eGFR) Category Normal	126 participants	125 participants	126 participants	377 participants
Ethnicity (NIH/OMB) Hispanic or Latino	37 Participants	41 Participants	44 Participants	122 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	265 Participants	253 Participants	251 Participants	769 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	70 Participants	63 Participants	61 Participants	194 Participants
Height	167.5 cm STANDARD_DEVIATION 11.22	167.8 cm STANDARD_DEVIATION 11.06	168.2 cm STANDARD_DEVIATION 10.3	167.8 cm STANDARD_DEVIATION 10.87
Race (NIH/OMB) American Indian or Alaska Native	37 participants	34 participants	35 participants	106 participants
Race (NIH/OMB) Asian	7 participants	5 participants	5 participants	17 participants
Race (NIH/OMB) Black or African American	95 participants	95 participants	100 participants	290 participants
Race (NIH/OMB) More than one race	5 participants	2 participants	4 participants	11 participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	3 participants	0 participants	0 participants	3 participants
Race (NIH/OMB) Unknown or Not Reported	0 participants	0 participants	0 participants	0 participants
Race (NIH/OMB) White	235 participants	225 participants	220 participants	680 participants
Region of Enrollment Argentina	13 participants	9 participants	9 participants	31 participants
Region of Enrollment Chile	12 participants	10 participants	9 participants	31 participants
Region of Enrollment Mexico	45 participants	44 participants	43 participants	132 participants
Region of Enrollment United States	302 participants	294 participants	295 participants	891 participants
Sex: Female, Male Female	175 Participants	174 Participants	173 Participants	522 Participants
Sex: Female, Male Male	197 Participants	183 Participants	183 Participants	563 Participants
Weight	89.35 kg STANDARD_DEVIATION 20.995	89.87 kg STANDARD_DEVIATION 21.281	90.66 kg STANDARD_DEVIATION 20.7	89.95 kg STANDARD_DEVIATION 20.981

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	66 / 372	72 / 357	56 / 356
serious Total, serious adverse events	4 / 372	8 / 357	6 / 356

Outcome results

Primary

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

The change in trough systolic blood pressure measured at week 8 or final visit relative to baseline. Systolic blood pressure is the average of the 3 serial trough sitting systolic blood pressure measurements.

Time frame: Baseline and Week 8.

Population: Full analysis set, all participants that took at least 1 dose of double-blind study drug and have a baseline and post-baseline value, with last observation carried forward.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Azilsartan Medoxomil 20-40mg Plus Chlorthalidone 12.5-25 mg QD	Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure.	-37.6 mmHg	Standard Deviation 0.83
Azilsartan Medoxomil 40-80mg Plus Chlorthalidone 12.5-25 mg QD	Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure.	-38.2 mmHg	Standard Deviation 0.85
Olmesartan Medoxomil 20-40mg/Hydrochlorothiazide 12.5-25mg QD	Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure.	-31.5 mmHg	Standard Deviation 0.84

Comparison: Analysis of Covariance (ANCOVA) model with treatment as a fixed effect and Baseline as a covariate.p-value: <0.00195% CI: [-8.4, -3.8]ANCOVA

Comparison: ANCOVA model with treatment as a fixed effect and Baseline as a covariate.p-value: <0.00195% CI: [-9.1, -4.4]ANCOVA

Secondary

Change From Baseline in 12-hr Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.

The change in the 0 to 12 hours-after-dosing mean diastolic blood pressure measured at Week 4 and Week 8 to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The mean consists of the average (arithmetic mean) of measurements collected at each time frame and includes all observations recorded over the subsequent 12 hours.