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Cardiovascular Safety of Febuxostat and Allopurinol in Participants With Gout and Cardiovascular Comorbidities (CARES) (CARES)

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ClinicalTrials.gov Identifier: NCT01101035
Recruitment Status : Completed
First Posted : April 9, 2010
Results First Posted : June 14, 2018
Last Update Posted : June 14, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Cardiovascular Disease
Interventions: Drug: Febuxostat
Drug: Allopurinol

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants took part in the study at 320 investigative sites in Canada, Mexico and United States from 23 April 2010 to 18 July 2017.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants with a diagnosis of gout and significant cardiovascular comorbidities were enrolled in a 1:1 ratio to receive either febuxostat or allopurinol.

Reporting Groups
  Description
Febuxostat Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months.
Allopurinol Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).

Participant Flow:   Overall Study
    Febuxostat   Allopurinol
STARTED   3101   3097 
COMPLETED   1704   1706 
NOT COMPLETED   1397   1391 
Adverse Event                191                172 
Major Protocol Deviation                52                46 
Lost to Follow-up                226                223 
Voluntary Withdrawal                595                587 
Reason not Specified                333                363 



  Baseline Characteristics

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 (FAS) included all participants who were randomized and received at least 1 dose of double-blind study medication.

Reporting Groups
  Description
Febuxostat Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months.
Allopurinol Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).
Total Total of all reporting groups

Baseline Measures
   Febuxostat   Allopurinol   Total 
Overall Participants Analyzed 
[Units: Participants]
 3098   3092   6190 
Age 
[Units: Years]
Mean (Standard Deviation)
     
Participants Analyzed   3098   3092   6190 
   64.6  (8.58)   65.0  (8.49)   64.8  (8.53) 
Age, Customized 
[Units: Participants]
Count of Participants
     
<65 years       
Participants Analyzed   3098   3092   6190 
<65 years   1584   1506   3090 
65 to <75 years       
Participants Analyzed   3098   3092   6190 
65 to <75 years   1094   1135   2229 
≥75 years       
Participants Analyzed   3098   3092   6190 
≥75 years   420   451   871 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Participants Analyzed   3098   3092   6190 
Female      494  15.9%      500  16.2%      994  16.1% 
Male      2604  84.1%      2592  83.8%      5196  83.9% 
Race/Ethnicity, Customized 
[Units: Participants]
Count of Participants
     
American Indian or Alaska Native       
Participants Analyzed   3098   3092   6190 
American Indian or Alaska Native   262   234   496 
Asian       
Participants Analyzed   3098   3092   6190 
Asian   92   96   188 
Black or African American       
Participants Analyzed   3098   3092   6190 
Black or African American   552   593   1145 
Native Hawaiian or Other Pacific Islander       
Participants Analyzed   3098   3092   6190 
Native Hawaiian or Other Pacific Islander   13   14   27 
White       
Participants Analyzed   3098   3092   6190 
White   2160   2140   4300 
Other       
Participants Analyzed   3098   3092   6190 
Other   19   15   34 
Race/Ethnicity, Customized 
[Units: Participants]
Count of Participants
     
Hispanic or Latino       
Participants Analyzed   3098   3092   6190 
Hispanic or Latino   539   521   1060 
Not Hispanic or Latino       
Participants Analyzed   3098   3092   6190 
Not Hispanic or Latino   2559   2571   5130 
Region of Enrollment 
[Units: Participants]
Count of Participants
     
Canada       
Participants Analyzed   3098   3092   6190 
Canada   68   72   140 
Mexico       
Participants Analyzed   3098   3092   6190 
Mexico   379   355   734 
United States       
Participants Analyzed   3098   3092   6190 
United States   2651   2665   5316 
Height 
[Units: Cm]
Mean (Standard Deviation)
     
Participants Analyzed   3098   3092   6190 
   172.9  (9.54)   173.0  (9.77)   173.0  (9.65) 
Weight [1] 
[Units: Kg]
Mean (Standard Deviation)
     
Participants Analyzed   3098   3087   6185 
   100.5  (22.47)   100.3  (22.89)   100.4  (22.68) 
[1] Here, number analyzed indicates participants who were evaluated for this baseline characteristic.
Body Mass Index (BMI) [1] [2] 
[Units: Kg/m^2]
Median (Full Range)
     
Participants Analyzed   3098   3087   6185 
   32.5 
 (18 to 73) 
 32.1 
 (17 to 75) 
 32.3 
 (17 to 75) 
[1] Body Mass Index = weight (kg)/[height (m)^2]
[2] Here, number analyzed indicates participants who were evaluated for this baseline characteristic.
BMI Categorical [1] 
[Units: Participants]
Count of Participants
     
<25       
Participants Analyzed   3098   3092   6190 
<25   201   201   402 
25-30       
Participants Analyzed   3098   3092   6190 
25-30   844   862   1706 
≥30       
Participants Analyzed   3098   3092   6190 
≥30   2053   2024   4077 
[1] Body Mass Index = weight (kg)/[height (m)^2]
Smoking History 
[Units: Participants]
Count of Participants
     
Never smoked       
Participants Analyzed   3098   3092   6190 
Never smoked   1175   1124   2299 
Ex-smoker       
Participants Analyzed   3098   3092   6190 
Ex-smoker   1533   1553   3086 
Current smoker       
Participants Analyzed   3098   3092   6190 
Current smoker   390   415   805 
Alcohol History 
[Units: Participants]
Count of Participants
     
Never drank       
Participants Analyzed   3098   3092   6190 
Never drank   792   784   1576 
Ex-drinker       
Participants Analyzed   3098   3092   6190 
Ex-drinker   805   812   1617 
Current drinker       
Participants Analyzed   3098   3092   6190 
Current drinker   1501   1496   2997 
Renal Function [1] 
[Units: Participants]
Count of Participants
     
Moderately Impaired       
Participants Analyzed   3098   3092   6190 
Moderately Impaired   1636   1631   3267 
Mildly Impaired       
Participants Analyzed   3098   3092   6190 
Mildly Impaired   1217   1231   2448 
Normal       
Participants Analyzed   3098   3092   6190 
Normal   239   228   467 
[1] Moderate renal impairment: eCLcr=30 to 59 mL/min; mild renal impairment: eCLcr=60 to 89 mL/min; normal: eCLcr ≥90 mL/min. Seven subjects with Baseline eCLcr <30 mL/min and 1 subject with missing Baseline eCLcr
History of Kidney Stone 
[Units: Participants]
Count of Participants
     
Yes       
Participants Analyzed   3098   3092   6190 
Yes   627   627   1254 
No       
Participants Analyzed   3098   3092   6190 
No   2471   2465   4936 
Use of Low Dose Aspirin [1] 
[Units: Participants]
Count of Participants
     
Yes       
Participants Analyzed   3098   3092   6190 
Yes   1496   1481   2977 
No       
Participants Analyzed   3098   3092   6190 
No   1602   1611   3213 
[1] Dosing <325 mg aspirin per day is considered as low-dose aspirin
Use of any Dose of Aspirin 
[Units: Participants]
Count of Participants
     
Yes       
Participants Analyzed   3098   3092   6190 
Yes   1894   1933   3827 
No       
Participants Analyzed   3098   3092   6190 
No   1204   1159   2363 
Use of Nonsteroidal Anti-Inflammatory Drug (NSAIDs) 
[Units: Participants]
Count of Participants
     
Yes       
Participants Analyzed   3098   3092   6190 
Yes   856   908   1764 
No       
Participants Analyzed   3098   3092   6190 
No   2242   2184   4426 
Use of Clopidogrel and Other Antiplatelet Drugs 
[Units: Participants]
Count of Participants
     
Yes       
Participants Analyzed   3098   3092   6190 
Yes   599   627   1226 
No       
Participants Analyzed   3098   3092   6190 
No   2499   2465   4964 


  Outcome Measures

1.  Primary:   Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis)   [ Time Frame: Up to last dose of study drug (approximately 83 months) ]

2.  Primary:   Percentage of Participants With Primary MACE Composite (Final Analysis)   [ Time Frame: Up to last dose of study drug (approximately 83 months) ]

3.  Secondary:   Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event   [ Time Frame: Up to last dose of study drug (approximately 83 months) ]

4.  Secondary:   Percentage of Participants With Cardiovascular (CV) Death   [ Time Frame: Up to last dose of study drug (approximately 83 months) ]

5.  Secondary:   Percentage of Participants With Non-fatal Myocardial Infarction (MI)   [ Time Frame: Up to last dose of study drug (approximately 83 months) ]

6.  Secondary:   Percentage of Participants With Non-fatal Stroke   [ Time Frame: Up to last dose of study drug (approximately 83 months) ]

7.  Secondary:   Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization   [ Time Frame: Up to last dose of study drug (approximately 83 months) ]


  Serious Adverse Events


  Other Adverse Events


  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.


  More Information

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.


Results Point of Contact:  
Name/Title: Medical Director
Organization: Takeda
phone: +1-877-825-3327
e-mail: trialdisclosures@takeda.com


Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01101035     History of Changes
Other Study ID Numbers: TMX-67_301
U1111-1114-4194 ( Registry Identifier: WHO )
First Submitted: April 7, 2010
First Posted: April 9, 2010
Results First Submitted: May 11, 2018
Results First Posted: June 14, 2018
Last Update Posted: June 14, 2018