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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT00818883
First received: January 7, 2009
Last updated: January 4, 2012
Last verified: January 2012
History of Changes
Results First Received: January 4, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Essential Hypertension
Interventions: Drug: Azilsartan medoxomil and chlorthalidone
Drug: Azilsartan medoxomil and hydrochlorothiazide

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants enrolled at 66 investigative sites in the Russian Federation and the United States from 20 January 2009 to 30 November 2009.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants with patients with moderate to severe essential hypertension were enrolled in one of 2, once-daily (QD) treatment groups.

Reporting Groups
  Description
Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD

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.
Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD

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.

Participant Flow:   Overall Study
    Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD     Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD  
STARTED     303     306  
COMPLETED     252     260  
NOT COMPLETED     51     46  
Adverse Event                 28                 19  
Protocol Violation                 2                 2  
Lost to Follow-up                 3                 2  
Withdrawal by Subject                 16                 14  
Lack of Efficacy                 0                 2  
Other                 2                 7  



  Baseline Characteristics
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Reporting Groups
  Description
Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD

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.
Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD

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.
Total Total of all reporting groups

Baseline Measures
    Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD     Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD     Total  
Number of Participants  
[units: participants]
 		  303     306     609  
Age  
[units: years]
Mean ± Standard Deviation 		  56.8  ± 10.79     55.9  ± 10.97     56.4  ± 10.88  
Age, Customized  
[units: participants]
 		     
<45 years     43     50     93  
Between 45 and 64 years     189     195     384  
≥65 years     71     61     132  
Gender  
[units: participants]
 		     
Female     158     155     313  
Male     145     151     296  
Ethnicity (NIH/OMB)  
[units: participants]
 		     
Hispanic or Latino     40     28     68  
Not Hispanic or Latino     173     184     357  
Unknown or Not Reported     90     94     184  
Race (NIH/OMB) [1]
[units: participants]
 		     
American Indian or Alaska Native     6     1     7  
Asian     3     2     5  
Native Hawaiian or Other Pacific Islander     1     0     1  
Black or African American     46     38     84  
White     252     265     517  
More than one race     5     0     5  
Unknown or Not Reported     0     0     0  
Region of Enrollment  
[units: participants]
 		     
United States     213     214     427  
Russian Federation     90     92     182  
Estimated glomerular filtration rate (eGFR) [2]
[units: participants]
 		     
Moderate impairment     23     24     47  
Mild impairment     180     184     364  
Normal     100     98     198  
Weight  
[units: kg]
Mean ± Standard Deviation 		  87.60  ± 19.181     90.61  ± 19.252     89.11  ± 19.260  
Height  
[units: cm]
Mean ± Standard Deviation 		  168.9  ± 10.08     168.8  ± 9.69     168.9  ± 9.88  
Body Mass Index (BMI)  
[units: kg/m2]
Median ± Standard Deviation 		  30.7  ± 6.12     31.8  ± 6.10     31.2  ± 6.13  
Chronic Kidney Disease (CKD) Status [3]
[units: participants]
 		  24     24     48  
Diabetes status  
[units: participants]
 		  31     35     66  
[1] Participants could choose more than 1 category for race. Participants who indicated more than 1 race category are included in each category indicated, and they are also included in the multiracial category. Thus, the sum of the number of participants by racial category may be greater than the total number of participants in the treatment group.
[2]

eGFR based on calculated creatinine clearance.

Categories:

Normal renal function (≥90 mL/min/1.73 m2); Mild renal impairment(≥60 to <90 mL/min/1.73 m2); Moderate renal impairment (≥30 to <60 mL/min/1.73 m2)
[3]

Participant was considered to have CKD if their eGFR was <60 ml/min/1.73 m2 or urinary albumin:creatinine ratio was >200 mg albumin/g creatinine at Screening.

Includes all randomized participants.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Change From Baseline in Trough, Sitting, Clinic Systolic Blood Pressure   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Show Outcome Measure 1

2.  Secondary:   Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Hide Outcome Measure 2

Measure Type Secondary
Measure Title Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure
Measure Description 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.  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, defined as all randomized participants who received at least 1 dose of active single-blind or double-blind study medication, with both a baseline value and at least 1 value during the treatment period, with last observation carried forward.

Reporting Groups
  Description
Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD

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.
Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD

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.

Measured Values
    Azilsartan Medoxomil 40 mg/Chlorthalidone 12.5 mg QD     Azilsartan Medoxomil 40 mg + Hydrochlorothiazide 12.5 mg QD  
Number of Participants Analyzed  
[units: participants]
 		  302     303  
Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure  
[units: mmHg]
Least Squares Mean ± Standard Error 		   
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 1 for Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure
Groups [1] All groups
Method [2] ANCOVA
P Value [3] <0.001
Mean Difference (Final Values) [4] -3.7
95% Confidence Interval ( -5.2 to -2.2 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  ANCOVA model with treatment group as a fixed effect and baseline value as a covariate was performed using Week 6 data.
[2] Other relevant information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  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.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure
Groups [1] All groups
Method [2] ANCOVA
P Value [3] <0.001
Mean Difference (Final Values) [4] -2.7
95% Confidence Interval ( -4.1 to -1.3 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  ANCOVA model with treatment group as a fixed effect and baseline value as a covariate was performed using Week 10 data.
[2] Other relevant information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  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.
[4] Other relevant estimation information:
  No text entered.



3.  Secondary:   Change From Baseline in Mean Trough Systolic Blood Pressure (22 to 24 Hours After Dosing) as Measured by Ambulatory Blood Pressure Monitoring.   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Show Outcome Measure 3

4.  Secondary:   Change From Baseline in Mean Trough Diastolic Blood Pressure (22 to 24 Hours After Dosing) as Measured by Ambulatory Blood Pressure Monitoring.   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Show Outcome Measure 4

5.  Secondary:   Change From Baseline in 24-hour Mean Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Show Outcome Measure 5

6.  Secondary:   Change From Baseline in 24-hour Mean Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Show Outcome Measure 6

7.  Secondary:   Change From Baseline in the Mean Daytime (6 AM to 10 PM) Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Show Outcome Measure 7

8.  Secondary:   Change From Baseline in the Mean Daytime (6 AM to 10 PM) Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Show Outcome Measure 8

9.  Secondary:   Change From Baseline in the Mean Nighttime (12 AM to 6 AM) Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Show Outcome Measure 9

10.  Secondary:   Change From Baseline in the Mean Nighttime (12 AM to 6 AM) Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring.   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Show Outcome Measure 10

11.  Secondary:   Change From Baseline in the Mean Systolic Blood Pressure at 0 to 12 Hours After Dosing as Measured by Ambulatory Blood Pressure Monitoring   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Show Outcome Measure 11

12.  Secondary:   Change From Baseline in the Mean Diastolic Blood Pressure at 0 to 12 Hours After Dosing as Measured by Ambulatory Blood Pressure Monitoring.   [ Time Frame: Baseline, Week 6 and Week 10. ]
  Show Outcome Measure 12

13.  Secondary:   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   [ Time Frame: Week 2, Week 4, Week 6, Week 8 and Week 10. ]
  Show Outcome Measure 13

14.  Secondary:   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.   [ Time Frame: Week 2, Week 4, Week 6, Week 8 and Week 10. ]
  Show Outcome Measure 14

15.  Secondary:   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   [ Time Frame: Week 2, Week 4, Week 6, Week 8 and Week 10. ]
  Show Outcome Measure 15


  Serious Adverse Events
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  Other Adverse Events
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.  


Results Point of Contact:  
Name/Title: Sr. VP, Clinical Science
Organization: Takeda Global Research and Development Center, Inc.
phone: 800-778-2860
e-mail: clinicaltrialregistry@tpna.com


No publications provided by Takeda

Publications automatically indexed to this study:


Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00818883     History of Changes
Other Study ID Numbers: TAK-491CLD_306, U1111-1112-7119
Study First Received: January 7, 2009
Results First Received: January 4, 2012
Last Updated: January 4, 2012
Health Authority: United States: Food and Drug Administration
Russia: Ministry of Health of the Russian Federation