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CompletedNCT00818883Updated Feb 7, 2012Results posted

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

A Phase 3 interventional study of Azilsartan medoxomil and chlorthalidone and Azilsartan medoxomil and hydrochlorothiazide in Essential Hypertension, sponsored by Takeda. Completed at 53 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2012-02-07.

Sponsored by Takeda · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
609
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

The purpose of this study is to compare the antihypertensive effect of chlorthalidone vs hydrochlorothiazide when each is used with azilsartan medoxomil, once daily (QD), in participants with moderate to severe essential hypertension.

Read the 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. 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. This trial is designed to compare chlorthalidone and hydrochlorothiazide when coadministered with azilsartan medoxomil.

Participants in this study will receive either chlorthalidone or hydrochlorothiazide in combination with azilsartan medoxomil. Total commitment time for this study is about 13 weeks. Participants will be required to wear a blood pressure monitor for three 24 hours periods during the study.

02

Conditions studied

  • Essential Hypertension

Keywords

  • Essential Hypertension
  • Hypertensive
  • Blood Pressure, High
  • Vascular Disease
  • Cardiovascular Disease
  • Drug Therapy
03

In context

Hypertension

6,689 studies on the registry are indexed under Hypertension; 965 are open to participants now.

This study's enrollment of 609 is above the median of 90 across 4,995 interventional studies indexed under Hypertension.

Browse Hypertension studies →

Lead sponsor

Takeda is the lead sponsor of 1,002 studies on the registry; 92 are open to participants now.

Of its 173 completed or terminated interventional studies of FDA-regulated products, 149 (86%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Is treated with antihypertensive therapy and has a post-washout mean sitting clinic SBP greater than or equal to 160 and less than or equal to 190 mm Hg on Day -1; or the participant has not received antihypertensive treatment within 28 days prior to Screening and has a mean sitting clinic SBP 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 agree to routinely use adequate contraception from Screening through 30 days after the last administered study drug dose.
  3. 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 significant.
  4. Is willing to discontinue current antihypertensive medications on Day -21 or Day -28 if the participant is on amlodipine or chlorthalidone.

Exclusion criteria

Exclusion Criteria:

  1. Has a mean sitting clinic diastolic blood pressure greater than 119 mm Hg on Day -1.
  2. Has a baseline 24-hour ambulatory blood pressure monitoring reading of insufficient quality.
  3. Works a night (third) shift (defined as 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 (less than 70% or greater than 130%) with study medication during the placebo run-in period.
  6. Has secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome).
  7. Has a recent history (within the last 6 months) of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.
  8. Has clinically significant cardiac conduction defects (ie, third-degree atrioventricular block, sick sinus syndrome, atrial fibrillation, or atrial flutter).
  9. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
  10. Has severe renal dysfunction or disease [based on estimated glomerular filtration rate less than 30 mL/min/1.73m2 at Screening].
  11. Has 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. (This criterion does not apply to those participants with basal cell or stage I squamous cell carcinoma of the skin).
  13. Has poorly-controlled type 1 or type 2 diabetes mellitus at Screening.
  14. Has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory).
  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 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. Currently participating in another investigational study or is receiving or has received any investigational compound within 30 days prior to Screening.
  20. Has a history of drug abuse or a history of alcohol abuse within the past 2 years.
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
609 participants (actual)

Study arms

  • Experimental
    Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD

    Drug: Azilsartan medoxomil and chlorthalidone

  • Experimental
    Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD

    Drug: Azilsartan medoxomil and hydrochlorothiazide

Interventions

  • DrugAzilsartan medoxomil and chlorthalidone

    Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablet, orally, once daily and hydrochlorothiazide placebo-matching tablets, orally, once daily for up to 10 weeks. For participants who do not achieve target blood pressure by Week 6, the dose of chlorthalidone will be increased for the remaining 4 weeks of treatment.

    Also known as: TAK-491, TAK-491CLD

  • DrugAzilsartan medoxomil and hydrochlorothiazide

    Azilsartan medoxomil 40 mg, tablets, orally, once daily and hydrochlorothiazide 12.5 mg, tablets, orally, once daily for up to 10 weeks. For participants who do not achieve target blood pressure by Week 6, the dose of hydrochlorothiazide will be increased for the remaining 4 weeks of treatment.

    Also known as: TAK-491, TAK-491CLD

06

What researchers measure

Primary outcomes

  1. Change From Baseline in Trough, Sitting, Clinic Systolic Blood Pressure

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

    Time frame: Baseline, Week 6 and Week 10.

Secondary outcomes

  1. Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure

    The change in sitting trough clinic diastolic blood pressure measured at each week indicated including final visit relative to baseline. Diastolic blood pressure is the average of the 3 serial trough sitting systolic blood pressure measurements.

    Time frame: Baseline, Week 6 and Week 10.

  2. Change From Baseline in Mean Trough Systolic Blood Pressure (22 to 24 Hours After Dosing) as Measured by Ambulatory Blood Pressure Monitoring.

    The change in trough systolic blood pressure measured at each week indicated including final visit 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.

    Time frame: Baseline, Week 6 and Week 10.

  3. Change From Baseline in 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 each week indicated including final visit 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.

    Time frame: Baseline, Week 6 and Week 10.

  4. Change From Baseline in 24-hour Mean Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.

    The change in 24-hour mean systolic blood pressure measured at each visit indicated including final visit 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.

    Time frame: Baseline, Week 6 and Week 10.

  5. Change From Baseline in 24-hour Mean Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.

    The change in 24-hour mean diastolic blood pressure measured at each visit indicated including final visit 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.

    Time frame: Baseline, Week 6 and Week 10.

  6. Change From Baseline 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 each visit including final visit 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.

    Time frame: Baseline, Week 6 and Week 10.

  7. Change From Baseline 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 each visit including final visit 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.

    Time frame: Baseline, Week 6 and Week 10.

  8. Change From Baseline 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 each visit indicated including final visit 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.

    Time frame: Baseline, Week 6 and Week 10.

  9. Change From Baseline 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 each visit indicated including final visit 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.

    Time frame: Baseline, Week 6 and Week 10.

  10. Change From Baseline 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 each visit including final visit 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.

    Time frame: Baseline, Week 6 and Week 10.

  11. Change From Baseline 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 each visit including final visit 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.

    Time frame: Baseline, Week 6 and Week 10.

  12. Percentage of Participants Who Reached Their Trough, Sitting, Clinic Systolic Blood Pressure Targets, Defined as <140 mm Hg for Participants Without Diabetes or Chronic Kidney Disease or <130 mm Hg for Participants With Diabetes or Chronic Kidney Disease

    Percentage of participants who achieve a clinic systolic blood pressure response measured at each week indicated, defined as \<140mm Hg without diabetes or chronic kidney disease or \<130/mm Hg with diabetes or chronic kidney disease. Systolic blood pressure is the average of the 3 serial trough sitting systolic blood pressure measurements.

    Time frame: Week 2, Week 4, Week 6, Week 8 and Week 10.

  13. Percentage of Participants Who Reached Their Trough, Sitting, Clinic Diastolic Blood Pressure Target, Defined as <90 mm Hg for Participants Without Diabetes or Chronic Kidney Disease or <80 mm Hg for Participants With Diabetes or Chronic Kidney Disease.

    Percentage of participants who achieve a clinic diastolic blood pressure response measured at each week indicated, defined as \<90 mm Hg for participants without diabetes or chronic kidney disease or \<80 mm Hg for participants with diabetes or chronic kidney disease. Diastolic blood pressure is the average of the 3 serial trough sitting diastolic blood pressure measurements.

    Time frame: Week 2, Week 4, Week 6, Week 8 and Week 10.

  14. Percentage of Participants Who Reached Their Trough, Sitting, Clinic Systolic and Diastolic Blood Pressure Targets, Defined as <140/90 mm Hg Without Diabetes or Chronic Kidney Disease or <130/80 mm Hg With Diabetes or Chronic Kidney Disease

    Percentage of participants who achieve both a clinic systolic and diastolic blood pressure response measured at each week indicated, defined as \<140/90 mm Hg for participants without diabetes or chronic kidney disease or \<130/80 mm Hg for participants with diabetes or chronic kidney disease\[GFR \<60 mL/min/1.73 m2 or urinary albumin:creatinine ratio (UACR) \>200 mg albumin/g creatinine at Screening.\] Systolic/diastolic blood pressure is the average of the 3 serial trough sitting systolic/diastolic blood pressure measurements.

    Time frame: Week 2, Week 4, Week 6, Week 8 and Week 10.

07

Results

Posted Feb 7, 2012

Participant flow

Participants enrolled at 66 investigative sites in the Russian Federation and the United States from 20 January 2009 to 30 November 2009.

Participant flow — Overall Study
MilestoneAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Started303306
Completed252260
Not completed5146
Withdrew: Adverse event2819
Withdrew: Protocol violation22
Withdrew: Lost to follow-up32
Withdrew: Withdrawal by subject1614
Withdrew: Lack of efficacy02
Withdrew: Other27

Outcome measures

PrimaryChange From Baseline in Trough, Sitting, Clinic Systolic Blood Pressure

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

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in Trough, Sitting, Clinic Systolic Blood Pressure
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=295; n=292)-35.1 ± 0.97-29.5 ± 0.98
Week 10 (n=295; n=292)-37.8 ± 0.91-32.8 ± 0.91
Statistical analysis
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = <0.001 (Overall type I error rate controlled using stepwise testing procedure. First treatment test done at Week 6. If statistically significant at significance level of 5%, then treatment comparison at Week 10 was performed. Tested at 5% significance level.) · Mean difference (final values): -5.6 · 95% CI -8.3 to -2.9
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = <0.001 (Overall type I error rate controlled using stepwise testing procedure. First treatment test done at Week 6. If statistically significant at significance level of 5%, then treatment comparison at Week 10 was performed. Tested at 5% significance level.) · Mean difference (final values): -5.0 · 95% CI -7.5 to -2.5
SecondaryChange From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure

The change in sitting trough clinic diastolic blood pressure measured at each week indicated including final visit relative to baseline. Diastolic blood pressure is the average of the 3 serial trough sitting systolic blood pressure measurements.

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=295; n=292)-15.0 ± 0.55-11.2 ± 0.55
Week 10 (n=295; n=292)-16.4 ± 0.50-13.7 ± 0.51
Statistical analysis
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = <0.001 (Overall type I error rate controlled using stepwise testing procedure. First treatment test done at Week 6. If statistically significant at significance level of 5%, then treatment comparison at Week 10 was performed. Tested at 5% significance level.) · Mean difference (final values): -3.7 · 95% CI -5.2 to -2.2
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = <0.001 (Overall type I error rate controlled using stepwise testing procedure. First treatment test done at Week 6. If statistically significant at significance level of 5%, then treatment comparison at Week 10 was performed. Tested at 5% significance level.) · Mean difference (final values): -2.7 · 95% CI -4.1 to -1.3
SecondaryChange From Baseline in Mean Trough Systolic Blood Pressure (22 to 24 Hours After Dosing) as Measured by Ambulatory Blood Pressure Monitoring.

The change in trough systolic blood pressure measured at each week indicated including final visit 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.

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in Mean Trough Systolic Blood Pressure (22 to 24 Hours After Dosing) as Measured by Ambulatory Blood Pressure Monitoring.
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=179, n=162)-25.7 ± 1.11-18.4 ± 1.16
Week 10 (n=227, n=230)-25.6 ± 0.91-21.4 ± 0.90
Statistical analysis
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = <0.001 (Tested at 5% significance level.) · Mean difference (final values): -7.3 · 95% CI -10.5 to -4.2
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = 0.001 (Tested at 5% significance level.) · Mean difference (final values): -4.2 · 95% CI -6.8 to -1.7
SecondaryChange From Baseline in 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 each week indicated including final visit 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.

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in Mean Trough Diastolic Blood Pressure (22 to 24 Hours After Dosing) as Measured by Ambulatory Blood Pressure Monitoring.
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=179; n=162)-15.2 ± 0.70-10.6 ± 0.74
Week 10 (n=227; n=230)-15.1 ± 0.63-12.7 ± 0.62
Statistical analysis
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = <0.001 (Tested at 5% significance level.) · Mean difference (final values): -4.3 · 95% CI -6.3 to -2.3
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = 0.006 (Tested at 5% significance level.) · Mean difference (final values): -2.4 · 95% CI -4.2 to -0.7
SecondaryChange From Baseline in 24-hour Mean Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.

The change in 24-hour mean systolic blood pressure measured at each visit indicated including final visit 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.

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in 24-hour Mean Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=179, n=162)-25.7 ± 0.92-19.9 ± 0.97
Week 10 (n=227, n=230)-26.6 ± 0.80-22.4 ± 0.79
Statistical analysis
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = <0.001 (Tested at 5% significance level.) · Mean difference (final values): -5.8 · 95% CI -8.4 to -3.2
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = <0.001 (Tested at 5% significance level.) · Mean difference (final values): -4.2 · 95% CI -6.4 to -2.0
SecondaryChange From Baseline in 24-hour Mean Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.

The change in 24-hour mean diastolic blood pressure measured at each visit indicated including final visit 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.

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in 24-hour Mean Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=179; n=162)-14.7 ± 0.59-10.9 ± 0.62
Week 10 (n=227; n=230)-15.2 ± 0.53-12.6 ± 0.53
Statistical analysis
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = <0.001 (Tested at 5% significance level.) · Mean difference (final values): -3.8 · 95% CI -5.5 to -2.1
  • Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD vs Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD · ANCOVA · p = <0.001 (Tested at 5% significance level.) · Mean difference (final values): -2.6 · 95% CI -4.1 to -1.1
SecondaryChange From Baseline 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 each visit including final visit 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.

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in the Mean Daytime (6 AM to 10 PM) Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=179; n=162)-27.0 ± 0.95-20.2 ± 1.00
Week 10 (n=227; n=230)-27.5 ± 0.82-22.8 ± 0.82
SecondaryChange From Baseline 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 each visit including final visit 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.

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in the Mean Daytime (6 AM to 10 PM) Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=179; n=162)-15.4 ± 0.62-11.1 ± 0.65
Week 10 (n=227; n=230)-15.8 ± 0.55-12.9 ± 0.55
SecondaryChange From Baseline 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 each visit indicated including final visit 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.

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in the Mean Nighttime (12 AM to 6 AM) Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=179; n=162)-21.8 ± 0.98-18.8 ± 1.03
Week 10 (n=227; n=230)-23.8 ± 0.87-21.1 ± 0.87
SecondaryChange From Baseline 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 each visit indicated including final visit 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.

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in the Mean Nighttime (12 AM to 6 AM) Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=179; n=162)-12.8 ± 0.64-10.3 ± 0.67
Week 10 (n=227; n=230)-13.8 ± 0.60-11.9 ± 0.60
SecondaryChange From Baseline 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 each visit including final visit 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.

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in the Mean Systolic Blood Pressure at 0 to 12 Hours After Dosing as Measured by Ambulatory Blood Pressure Monitoring
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=179; n=162)-27.7 ± 0.99-20.6 ± 1.04
Week 10 (n=227; n=230)-28.0 ± 0.86-23.2 ± 0.86
SecondaryChange From Baseline 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 each visit including final visit 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.

Time frame:
Baseline, Week 6 and Week 10.
Reported as:
Least squares mean · mmHg
Change From Baseline in the Mean Diastolic Blood Pressure at 0 to 12 Hours After Dosing as Measured by Ambulatory Blood Pressure Monitoring.
mmHgAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 6 (n=179; n=162)-15.7 ± 0.65-11.1 ± 0.68
Week 10 (n=227; n=230)-16.0 ± 0.59-12.9 ± 0.58
SecondaryPercentage of Participants Who Reached Their Trough, Sitting, Clinic Systolic Blood Pressure Targets, Defined as <140 mm Hg for Participants Without Diabetes or Chronic Kidney Disease or <130 mm Hg for Participants With Diabetes or Chronic Kidney Disease

Percentage of participants who achieve a clinic systolic blood pressure response measured at each week indicated, defined as \<140mm Hg without diabetes or chronic kidney disease or \<130/mm Hg with diabetes or chronic kidney disease. Systolic blood pressure is the average of the 3 serial trough sitting systolic blood pressure measurements.

Time frame:
Week 2, Week 4, Week 6, Week 8 and Week 10.
Reported as:
Number · percentage of participants
Percentage of Participants Who Reached Their Trough, Sitting, Clinic Systolic Blood Pressure Targets, Defined as <140 mm Hg for Participants Without Diabetes or Chronic Kidney Disease or <130 mm Hg for Participants With Diabetes or Chronic Kidney Disease
percentage of participantsAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 2 (n=283; n=276)33.234.1
Week 4 (n=292; n=289)68.254.7
Week 6 (n=295; n=292)71.958.2
Week 8 (n=295; n=292)79.765.4
Week 10 (n=295; n=292)76.969.9
SecondaryPercentage of Participants Who Reached Their Trough, Sitting, Clinic Diastolic Blood Pressure Target, Defined as <90 mm Hg for Participants Without Diabetes or Chronic Kidney Disease or <80 mm Hg for Participants With Diabetes or Chronic Kidney Disease.

Percentage of participants who achieve a clinic diastolic blood pressure response measured at each week indicated, defined as \<90 mm Hg for participants without diabetes or chronic kidney disease or \<80 mm Hg for participants with diabetes or chronic kidney disease. Diastolic blood pressure is the average of the 3 serial trough sitting diastolic blood pressure measurements.

Time frame:
Week 2, Week 4, Week 6, Week 8 and Week 10.
Reported as:
Number · percentage of participants
Percentage of Participants Who Reached Their Trough, Sitting, Clinic Diastolic Blood Pressure Target, Defined as <90 mm Hg for Participants Without Diabetes or Chronic Kidney Disease or <80 mm Hg for Participants With Diabetes or Chronic Kidney Disease.
percentage of participantsAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 2 (n=283; n=276)49.141.3
Week 4 (n=292; n=289)71.957.4
Week 6 (n=295; n=292)76.659.2
Week 8 (n=295; n=292)81.472.3
Week 10 (n=295; n=292)82.775.0
SecondaryPercentage of Participants Who Reached Their Trough, Sitting, Clinic Systolic and Diastolic Blood Pressure Targets, Defined as <140/90 mm Hg Without Diabetes or Chronic Kidney Disease or <130/80 mm Hg With Diabetes or Chronic Kidney Disease

Percentage of participants who achieve both a clinic systolic and diastolic blood pressure response measured at each week indicated, defined as \<140/90 mm Hg for participants without diabetes or chronic kidney disease or \<130/80 mm Hg for participants with diabetes or chronic kidney disease\[GFR \<60 mL/min/1.73 m2 or urinary albumin:creatinine ratio (UACR) \>200 mg albumin/g creatinine at Screening.\] Systolic/diastolic blood pressure is the average of the 3 serial trough sitting systolic/diastolic blood pressure measurements.

Time frame:
Week 2, Week 4, Week 6, Week 8 and Week 10.
Reported as:
Number · percentage of participants
Percentage of Participants Who Reached Their Trough, Sitting, Clinic Systolic and Diastolic Blood Pressure Targets, Defined as <140/90 mm Hg Without Diabetes or Chronic Kidney Disease or <130/80 mm Hg With Diabetes or Chronic Kidney Disease
percentage of participantsAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Week 2 (n=283; n=276)27.224.6
Week 4 (n=292; n=289)58.645.3
Week 6 (n=295; n=292)64.145.9
Week 8 (n=295; n=292)72.559.2
Week 10 (n=295; n=292)71.562.3

Adverse events

Collected over Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious adverse event) after the last dose of double-blind study drug.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD—6/302 (2%)79/302 (26.2%)
Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD—5/303 (1.7%)68/303 (22.4%)
Most frequent serious events
Showing 10 of 15
Most frequent serious events
EventAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Angina unstableCardiac disorders1/3020/303
Coronary artery occlusionCardiac disorders1/3020/303
Coronary artery stenosisCardiac disorders1/3020/303
Gastrointestinal haemorrhageGastrointestinal disorders1/3020/303
Sudden deathGeneral disorders1/3021/303
Chest discomfortGeneral disorders1/3020/303
Blood creatinine increasedInvestigations1/3020/303
Breast cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)1/3020/303
Renal failure chronicRenal and urinary disorders1/3020/303
Chest painGeneral disorders0/3021/303
Most frequent other events
Most frequent other events
EventAzilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD
Blood creatinine increasedInvestigations38/30227/303
DizzinessNervous system disorders37/30232/303
HeadacheNervous system disorders16/30216/303

Baseline characteristics

Age Continuous
Age Continuous(years)Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QDTotal
Mean56.8 ± 10.7955.9 ± 10.9756.4 ± 10.88
Age, Customized
Age, Customized(participants)Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QDTotal
<45 years435093
Between 45 and 64 years189195384
≥65 years7161132
Sex: Female, Male
Sex: Female, Male(Participants)Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QDTotal
Female158155313
Male145151296
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QDTotal
Hispanic or Latino402868
Not Hispanic or Latino173184357
Unknown or Not Reported9094184
Race (NIH/OMB)
Race (NIH/OMB)(participants)Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QDTotal
American Indian or Alaska Native617
Asian325
Native Hawaiian or Other Pacific Islander101
Black or African American463884
White252265517
More than one race505
Unknown or Not Reported000
Region of Enrollment
Region of Enrollment(participants)Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QDTotal
United States213214427
Russian Federation9092182
Estimated glomerular filtration rate (eGFR)
Estimated glomerular filtration rate (eGFR)(participants)Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QDTotal
Moderate impairment232447
Mild impairment180184364
Normal10098198
Weight
Weight(kg)Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QDAzilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QDTotal
Mean87.60 ± 19.18190.61 ± 19.25289.11 ± 19.260

4 further baseline measures are reported on the registry.

08

Study locations

53 sites
  • Birmingham, Alabama, United States
  • Gulf Shores, Alabama, United States
  • Scottsboro, Alabama, United States
  • Gilbert, Arizona, United States
  • Sierra Vista, Arizona, United States
  • Paramount, California, United States
  • Sacramento, California, United States
  • San Diego, California, United States
  • Colorado Springs, Colorado, United States
  • Wheat Ridge, Colorado, United States
  • Milford, Connecticut, United States
  • Adventura, Florida, United States
  • Aventura, Florida, United States
  • Brooksville, Florida, United States
  • Crystal River, Florida, United States
  • DeLand, Florida, United States
  • Doral, Florida, United States
  • Miami, Florida, United States
  • Naranja, Florida, United States
  • Sarasota, Florida, United States
  • Tampa, Florida, United States
  • West Palm Beach, Florida, United States
  • Winter Haven, Florida, United States
  • Atlanta, Georgia, United States
  • Stockbridge, Georgia, United States
  • Suwanee, Georgia, United States
  • Huntsville, Illinois, United States
  • Bloomington, Indiana, United States
  • Valparaiso, Indiana, United States
  • Crestview Hills, Kentucky, United States
  • Lexington, Kentucky, United States
  • West Yarmouth, Massachusetts, United States
  • Ann Arbor, Michigan, United States
  • St. Louis, Missouri, United States
  • St. Peters, Missouri, United States
  • New Windsor, New York, United States
  • Asheboro, North Carolina, United States
  • Cincinnati, Ohio, United States
  • Kettering, Ohio, United States
  • Downingtown, Pennsylvania, United States
  • Lancaster, Pennsylvania, United States
  • Lansdale, Pennsylvania, United States
  • Pittsburgh, Pennsylvania, United States
  • Goose Creek, South Carolina, United States
  • Taylors, South Carolina, United States
  • Bryan, Texas, United States
  • San Antonio, Texas, United States
  • Ettrick, Virginia, United States
  • Seattle, Washington, United States
  • Madison, Wisconsin, United States
  • Moscow, Russian Federation
  • Perm, Russian Federation
  • St. Petersburg, Russian Federation
09

References and documents

Publications

  • Bakris GL, Sica D, White WB, Cushman WC, Weber MA, Handley A, Song E, Kupfer S. Antihypertensive efficacy of hydrochlorothiazide vs chlorthalidone combined with azilsartan medoxomil. Am J Med. 2012 Dec;125(12):1229.e1-1229.e10. doi: 10.1016/j.amjmed.2012.05.023. Epub 2012 Aug 30. PubMed 22939358 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Feb 7, 2012, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00818883
Lead sponsor
Takeda
Responsible party
Sponsor
First posted
Jan 8, 2009
Start date
Feb 2009
Primary completion
Nov 2009
Completion
Nov 2009
Results posted
Feb 7, 2012
Last update
Feb 7, 2012

Study contacts

Executive Medical Director
study director · Takeda

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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