A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation (ATHENA)

This study has been completed.
Sponsor:
Information provided by:
Sanofi
ClinicalTrials.gov Identifier:
NCT00174785
First received: September 13, 2005
Last updated: January 5, 2010
Last verified: January 2010
Results First Received: July 24, 2009  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Prevention
Conditions: Atrial Fibrillation
Atrial Flutter
Interventions: Drug: dronedarone (SR33589)
Drug: placebo

  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
Enrollment of patients started on June 29, 2005 and was completed on December 30, 2006. The study was conducted at 551 centers in 37 countries. The common study end date ensuring a minimum planned follow-up of one year was December 30th, 2007.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Participant Flow:   Overall Study
    Dronedarone 400mg Bid     Placebo  
STARTED     2301 [1]   2327 [2]
COMPLETED     1605 [3]   1611 [3]
NOT COMPLETED     696     716  
Adverse Event                 293                 191  
Protocol Violation                 14                 14  
Withdrawal by Subject                 173                 175  
Atrial Fibrillation/Flutter recurrence                 110                 167  
Prohibited antiarrhythmic medication                 39                 88  
Other prohibited medication                 5                 3  
Family request                 6                 8  
Not pre-specified/Not coded                 56                 70  
[1] randomized patients; among them, 10 patients did not receive any study drug in the dronedarone group
[2] randomized patients; among them, 14 patients did not receive any study drug in the placebo group
[3] completed study drug



  Baseline Characteristics
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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.
No text entered.

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets
Total Total of all reporting groups

Baseline Measures
    Dronedarone 400mg Bid     Placebo     Total  
Number of Participants  
[units: participants]
  2301     2327     4628  
Age, Customized  
[units: participants]
     
18 to < 65 years     431     442     873  
65 to < 75 years     923     907     1830  
>= 75 years     947     978     1925  
Age  
[units: years]
Mean ± Standard Deviation
  71.6  ± 8.9     71.7  ± 9.0     71.6  ± 9.0  
Gender  
[units: participants]
     
Female     1131     1038     2169  
Male     1170     1289     2459  



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   First Hospitalization for Cardiovascular Reason or Death From Any Cause   [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ]

Measure Type Primary
Measure Title First Hospitalization for Cardiovascular Reason or Death From Any Cause
Measure Description The primary event is the first hospitalization for cardiovascular reason or death from any cause, whichever is earlier, as assessed by the investigator. The primary efficacy analysis is performed on the time from randomization to this primary event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame minimum follow-up duration: 1 year ; maximum: 2.5 years  
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.
All efficacy analyses were performed on the "all randomized patients" population including all patients randomized irrespective of whether the patient actually received any drug or complied with the study protocol.

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Measured Values
    Dronedarone 400mg Bid     Placebo  
Number of Participants Analyzed  
[units: participants]
  2301     2327  
First Hospitalization for Cardiovascular Reason or Death From Any Cause  
[units: participants]
  734     917  


Statistical Analysis 1 for First Hospitalization for Cardiovascular Reason or Death From Any Cause
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.76
95% Confidence Interval ( 0.69 to 0.84 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method 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:
  Cumulative incidence functions in each treatment group were calculated using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. The primary comparison was performed at the 5% level using a 2-sided Log rank test.
[4] Other relevant estimation information:
  The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of first hospitalization for cardiovascular reason or death for the dronedarone group compared with the placebo group.



2.  Secondary:   Death From Any Cause   [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ]

Measure Type Secondary
Measure Title Death From Any Cause
Measure Description The considered event is death from any cause. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame minimum follow-up duration: 1 year ; maximum: 2.5 years  
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.
«All randomized patients» population

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Measured Values
    Dronedarone 400mg Bid     Placebo  
Number of Participants Analyzed  
[units: participants]
  2301     2327  
Death From Any Cause  
[units: participants]
  116     139  


Statistical Analysis 1 for Death From Any Cause
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.18
Hazard Ratio (HR) [4] 0.84
95% Confidence Interval ( 0.66 to 1.08 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method 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:
  Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. Hierarchical procedure applied to secondary efficacy endpoints testing to protect the global type I error.
[4] Other relevant estimation information:
  The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of death from any cause for the dronedarone group compared with the placebo group.



3.  Secondary:   First Hospitalization for Cardiovascular Reason   [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ]

Measure Type Secondary
Measure Title First Hospitalization for Cardiovascular Reason
Measure Description The considered event is the first hospitalization for cardiovascular reason, as assessed by the Investigator. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame minimum follow-up duration: 1 year ; maximum: 2.5 years  
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.
«All randomized patients» population

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Measured Values
    Dronedarone 400mg Bid     Placebo  
Number of Participants Analyzed  
[units: participants]
  2301     2327  
First Hospitalization for Cardiovascular Reason  
[units: participants]
  675     859  


Statistical Analysis 1 for First Hospitalization for Cardiovascular Reason
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.74
95% Confidence Interval ( 0.67 to 0.82 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method 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:
  Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. Hierarchical procedure applied to secondary efficacy endpoints testing to protect the global type I error.
[4] Other relevant estimation information:
  The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of first hospitalization for cardiovascular reason for the dronedarone group compared with the placebo group.



4.  Secondary:   Cardiovascular Death   [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ]

Measure Type Secondary
Measure Title Cardiovascular Death
Measure Description The considered event is cardiovascular death, as assessed by the Investigator. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame minimum follow-up duration: 1 year ; maximum: 2.5 years  
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.
«All randomized patients» population

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Measured Values
    Dronedarone 400mg Bid     Placebo  
Number of Participants Analyzed  
[units: participants]
  2301     2327  
Cardiovascular Death  
[units: participants]
  65     94  


Statistical Analysis 1 for Cardiovascular Death
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.025
Hazard Ratio (HR) [4] 0.70
95% Confidence Interval ( 0.51 to 0.96 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method 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:
  Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. Hierarchical procedure applied to secondary efficacy endpoints testing to protect the global type I error.
[4] Other relevant estimation information:
  The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of cardiovascular death for the dronedarone group compared with the placebo group.



5.  Other Pre-specified:   Adjudicated Cardiovascular Death   [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ]

Measure Type Other Pre-specified
Measure Title Adjudicated Cardiovascular Death
Measure Description The considered event is cardiovascular death, as assessed by the blinded adjudication of the Steering Committee. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame minimum follow-up duration: 1 year ; maximum: 2.5 years  
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.
«All randomized patients» population

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Measured Values
    Dronedarone 400mg Bid     Placebo  
Number of Participants Analyzed  
[units: participants]
  2301     2327  
Adjudicated Cardiovascular Death  
[units: participants]
  63     90  


Statistical Analysis 1 for Adjudicated Cardiovascular Death
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.03
Hazard Ratio (HR) [4] 0.71
95% Confidence Interval ( 0.51 to 0.98 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method 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:
  Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. The comparison was performed at the 5% level using a 2-sided Log rank
[4] Other relevant estimation information:
  The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of adjudicated cardiovascular death for the dronedarone group compared with the placebo group.




  Serious Adverse Events


  Other Adverse Events


  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: International Clinical Development (ICD), Clinical Study Director
Organization: sanofi-aventis
e-mail: GV-Contact-us@sanofi-aventis.com


Publications of Results:
Other Publications:
Publications automatically indexed to this study:

Responsible Party: International Clinical Development - Study Director, sanofi-aventis
ClinicalTrials.gov Identifier: NCT00174785     History of Changes
Other Study ID Numbers: EFC5555
Study First Received: September 13, 2005
Results First Received: July 24, 2009
Last Updated: January 5, 2010
Health Authority: United States: Food and Drug Administration
Netherlands: Medicines Evaluation Board (MEB)
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)