Atrial Fibrillation
Conditions
Brief summary
Primary Objective: * Demonstrate the efficacy of Dronedarone in preventing major cardiovascular events (stroke, systemic arterial embolism, myocardial infarction or cardiovascular death) or unplanned cardiovascular hospitalization or death from any cause in patients with permanent Atrial Fibrillation \[AF\] and additional risk factors Secondary Objective: * Demonstrate the efficacy of Dronedarone in preventing cardiovascular death This was an event-driven study where a common study end date \[CSED\] was to be determined by Steering Committee based on the number of events (stroke, systemic arterial embolism, myocardial infarction or cardiovascular death).
Detailed description
The study period per participant was variable depending on the enrollment in the study. A final follow-up visit had to occur within 1 month after the CSED.
Interventions
DRUGDronedarone
Film-coated tablet Oral administration under fed conditions (during breakfast and dinner)
film-coated tablet strictly identical in appearance Oral administration under fed conditions (during breakfast and dinner)
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Permanent AF defined by the presence of all of the following criteria: * Availability of one 12-lead ECG not more than 14 days prior to randomization showing that the patient is in AF or atrial flutter; * Availability of documentation (including either rhythm strips or medical report of the rhythm) showing that the patient was in AF or atrial flutter at least 6 months prior to randomization; * No evidence of sinus rhythm in the period between these two documentations of AF; * Decision of the patient and physician to allow AF to continue without further efforts to restore sinus rhythm. * At least one of the following risk criteria: * Coronary artery disease; * Prior stroke or Transient Ischemic Attack \[TIA\]; * Symptomatic heart failure; * Left ventricular ejection fraction \[LVEF\] less or equal to 0.40; * Peripheral arterial occlusive disease; * Aged 75 years or older with both hypertension and diabetes mellitus.
Exclusion criteria
* Paroxysmal AF; * Persistent AF without a decision to allow AF to continue without further efforts to restore sinus rhythm; * Heart failure of New-York Heart Association \[NYHA\] class IV or recent unstable NYHA class III. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Co-primary Outcome (Cumulative Incidence Function) | From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) | Time to first co-primary outcome was defined as the time from randomization to the first event among stroke, systemic arterial embolism, MI or cardiovascular death. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation. |
| Overview of the Two Co-primary Outcomes | From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) | First co-primary outcome was defined as the first event among stroke, systemic arterial embolism, Myocardial Infarctions \[MI\], or cardiovascular death. Second co-primary outcome was defined as the first event among unscheduled cardiovascular hospitalization or death from any cause. Both co-primary outcomes were determined based on the central review and adjudication by a blinded Adjudication Committee of all reported deaths (from any cause), MI, systemic arterial embolisms, strokes, Transient Ischemic Attacks \[TIA\], Heart Failure hospitalization and unplanned hospitalisations for cardiovascular cause. |
| Time to Second Co-primary Outcome (Cumulative Incidence Function) | From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) | Time to second co-primary outcome was defined as the time from randomization to the first event among unscheduled cardiovascular hospitalization or death from any cause. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Cardiovascular Death (Cumulative Incidence Function) | From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) | Time to cardiovascular death was defined as the time from randomization to the death. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation. |
| Deaths | From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) | Deaths were classified according to the primary cause of death. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overview of Cardiovascular Events | From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year) | — |
| Overview of Adverse Events [AE] | from first study drug intake up to 10 days after the last study drug intake | AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Malaysia, Mexico, Netherlands, New Zealand, Norway, Poland, Romania, Russia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Recruitment initiated in July 2010 was discontinued on July 6, 2011 upon recommendations of the Data Monitoring Committee due to an increased number of observed cardiovascular events in the Dronedarone group. The common study end date \[CSED\] was defined as July 15, 2011. At that time 494 sites in 37 countries had enrolled at least one patient.
Pre-assignment details
Assignment to groups was done centrally using an Interactive Voice Response System \[IVRS\] or an Interactive Web Response System \[IWRS\] in a 1:1 ratio. A total of 3236 participants were randomized at 489 sites (instead of 10800 as initially planned). The median duration of their participation in the study was 3.5 months.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo twice daily until the CSED (median treatment duration of 87.5 days) | 1,617 |
| Dronedarone Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days) | 1,619 |
| Total | 3,236 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 15 | 27 |
| Overall Study | Lost to Follow-up | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Dronedarone | Total |
|---|---|---|---|
| Age Continuous | 75.0 years STANDARD_DEVIATION 5.9 | 75.0 years STANDARD_DEVIATION 5.9 | 75.0 years STANDARD_DEVIATION 5.9 |
| CHADS2 Score < 2 | 172 participants | 191 participants | 363 participants |
| CHADS2 Score ≥ 2 | 1444 participants | 1427 participants | 2871 participants |
| CHADS2 Score Unavailable | 1 participants | 1 participants | 2 participants |
| New York Heart Association [NYHA] class No congestive heart failure [CHF] | 535 participants | 512 participants | 1047 participants |
| New York Heart Association [NYHA] class NYHA Class I | 209 participants | 234 participants | 443 participants |
| New York Heart Association [NYHA] class NYHA Class II | 749 participants | 732 participants | 1481 participants |
| New York Heart Association [NYHA] class NYHA Class III | 124 participants | 141 participants | 265 participants |
| Permanent atrial fibrillation [AF] history > 2 years | 1124 participants | 1119 participants | 2243 participants |
| Permanent atrial fibrillation [AF] history 6 months to 2 years | 490 participants | 498 participants | 988 participants |
| Permanent atrial fibrillation [AF] history Unknown | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Asia | 53 participants | 47 participants | 100 participants |
| Region of Enrollment Eastern Europe | 495 participants | 488 participants | 983 participants |
| Region of Enrollment North America | 281 participants | 266 participants | 547 participants |
| Region of Enrollment Rest of the word | 102 participants | 107 participants | 209 participants |
| Region of Enrollment South America | 227 participants | 236 participants | 463 participants |
| Region of Enrollment Western Europe | 459 participants | 475 participants | 934 participants |
| Sex: Female, Male Female | 577 Participants | 568 Participants | 1145 Participants |
| Sex: Female, Male Male | 1040 Participants | 1051 Participants | 2091 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 1,609 | 100 / 1,614 |
| serious Total, serious adverse events | 77 / 1,609 | 113 / 1,614 |
Outcome results
Primary
Overview of the Two Co-primary Outcomes
First co-primary outcome was defined as the first event among stroke, systemic arterial embolism, Myocardial Infarctions \[MI\], or cardiovascular death. Second co-primary outcome was defined as the first event among unscheduled cardiovascular hospitalization or death from any cause. Both co-primary outcomes were determined based on the central review and adjudication by a blinded Adjudication Committee of all reported deaths (from any cause), MI, systemic arterial embolisms, strokes, Transient Ischemic Attacks \[TIA\], Heart Failure hospitalization and unplanned hospitalisations for cardiovascular cause.
Time frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)
Population: Intent-to-treat population: All randomized participants considered in the treatment group to which they were randomized regardless of the treatment they actually received
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Overview of the Two Co-primary Outcomes | First co-primary endpoint | 19 participants |
| Placebo | Overview of the Two Co-primary Outcomes | Second co-primary endpoint | 67 participants |
| Dronedarone | Overview of the Two Co-primary Outcomes | First co-primary endpoint | 43 participants |
| Dronedarone | Overview of the Two Co-primary Outcomes | Second co-primary endpoint | 127 participants |
Primary
Time to First Co-primary Outcome (Cumulative Incidence Function)
Time to first co-primary outcome was defined as the time from randomization to the first event among stroke, systemic arterial embolism, MI or cardiovascular death. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.
Time frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)
Population: Intent-to-treat population as previously defined
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 14 days | 0.002 proportion of participants |
| Placebo | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 30 days | 0.003 proportion of participants |
| Placebo | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 90 days | 0.007 proportion of participants |
| Placebo | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 180 days | 0.013 proportion of participants |
| Placebo | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 270 days | 0.038 proportion of participants |
| Placebo | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 360 days | 0.038 proportion of participants |
| Dronedarone | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 270 days | 0.045 proportion of participants |
| Dronedarone | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 14 days | 0.009 proportion of participants |
| Dronedarone | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 180 days | 0.042 proportion of participants |
| Dronedarone | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 30 days | 0.013 proportion of participants |
| Dronedarone | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 360 days | 0.045 proportion of participants |
| Dronedarone | Time to First Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 90 days | 0.021 proportion of participants |
Comparison: As a consequence of the early termination of the study, the analysis was performed for information only without any adjustment.p-value: 0.001995% CI: [1.337, 3.936]Log Rank
Primary
Time to Second Co-primary Outcome (Cumulative Incidence Function)
Time to second co-primary outcome was defined as the time from randomization to the first event among unscheduled cardiovascular hospitalization or death from any cause. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.
Time frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)
Population: Intent-to-treat population as previously defined
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 14 days | 0.005 proportion of participants |
| Placebo | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 30 days | 0.014 proportion of participants |
| Placebo | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 90 days | 0.033 proportion of participants |
| Placebo | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 180 days | 0.059 proportion of participants |
| Placebo | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 270 days | 0.099 proportion of participants |
| Placebo | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 360 days | 0.099 proportion of participants |
| Dronedarone | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 270 days | 0.137 proportion of participants |
| Dronedarone | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 14 days | 0.020 proportion of participants |
| Dronedarone | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 180 days | 0.110 proportion of participants |
| Dronedarone | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 30 days | 0.034 proportion of participants |
| Dronedarone | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 360 days | 0.137 proportion of participants |
| Dronedarone | Time to Second Co-primary Outcome (Cumulative Incidence Function) | Cumulative incidence at 90 days | 0.069 proportion of participants |
Comparison: As a consequence of the early termination of the study, the analysis was performed for information only without any adjustment.p-value: <0.000195% CI: [1.448, 2.617]Log Rank
Secondary
Deaths
Deaths were classified according to the primary cause of death.
Time frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)
Population: Intent-to-treat population as previously defined
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Deaths | Any death | 13 participants |
| Placebo | Deaths | - Cardiovascular death | 10 participants |
| Placebo | Deaths | --- Cardiac arrhythmic death | 4 participants |
| Dronedarone | Deaths | Any death | 25 participants |
| Dronedarone | Deaths | - Cardiovascular death | 21 participants |
| Dronedarone | Deaths | --- Cardiac arrhythmic death | 13 participants |
Secondary
Time to Cardiovascular Death (Cumulative Incidence Function)
Time to cardiovascular death was defined as the time from randomization to the death. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.
Time frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)
Population: Intent-to-treat population as previously defined
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 14 days | 0.001 proportion of participants |
| Placebo | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 30 days | 0.003 proportion of participants |
| Placebo | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 90 days | 0.004 proportion of participants |
| Placebo | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 180 days | 0.004 proportion of participants |
| Placebo | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 270 days | 0.027 proportion of participants |
| Placebo | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 360 days | 0.027 proportion of participants |
| Dronedarone | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 270 days | 0.026 proportion of participants |
| Dronedarone | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 14 days | 0.003 proportion of participants |
| Dronedarone | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 180 days | 0.022 proportion of participants |
| Dronedarone | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 30 days | 0.005 proportion of participants |
| Dronedarone | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 360 days | 0.026 proportion of participants |
| Dronedarone | Time to Cardiovascular Death (Cumulative Incidence Function) | Cumulative incidence at 90 days | 0.008 proportion of participants |
Comparison: As a consequence of the early termination of the study, the analysis was performed for information only without any adjustment.p-value: 0.04695% CI: [0.996, 4.49]Log Rank
Other Pre-specified
Overview of Adverse Events [AE]
AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Time frame: from first study drug intake up to 10 days after the last study drug intake
Population: Safety population: all randomized and treated participants. Participants were considered according to the treatment actually received. Consequently the participant randomized to the placebo group who received Dronedarone was included in the Dronedarone group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Overview of Adverse Events [AE] | - Any serious AE | 77 participants |
| Placebo | Overview of Adverse Events [AE] | - Any AE leading to treatment discontinuation | 80 participants |
| Placebo | Overview of Adverse Events [AE] | - Any AE leading to death | 0 participants |
| Placebo | Overview of Adverse Events [AE] | - Any AE leading to hospitalization | 71 participants |
| Placebo | Overview of Adverse Events [AE] | Any AE | 600 participants |
| Dronedarone | Overview of Adverse Events [AE] | - Any AE leading to hospitalization | 95 participants |
| Dronedarone | Overview of Adverse Events [AE] | Any AE | 797 participants |
| Dronedarone | Overview of Adverse Events [AE] | - Any serious AE | 113 participants |
| Dronedarone | Overview of Adverse Events [AE] | - Any AE leading to death | 4 participants |
| Dronedarone | Overview of Adverse Events [AE] | - Any AE leading to treatment discontinuation | 212 participants |
Other Pre-specified
Overview of Cardiovascular Events
Time frame: From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)
Population: Intent-to-treat population as previously defined
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Overview of Cardiovascular Events | MI or unstable angina pectoris | 8 participants |
| Placebo | Overview of Cardiovascular Events | - MI | 2 participants |
| Placebo | Overview of Cardiovascular Events | Stroke | 10 participants |
| Placebo | Overview of Cardiovascular Events | - Ischemic stroke | 9 participants |
| Placebo | Overview of Cardiovascular Events | Systemic arterial embolism | 0 participants |
| Placebo | Overview of Cardiovascular Events | Episode of heart failure | 55 participants |
| Placebo | Overview of Cardiovascular Events | - Hospitalization due to heart failure | 24 participants |
| Placebo | Overview of Cardiovascular Events | Unplanned hospitalization for cardiovascular cause | 59 participants |
| Dronedarone | Overview of Cardiovascular Events | Unplanned hospitalization for cardiovascular cause | 113 participants |
| Dronedarone | Overview of Cardiovascular Events | MI or unstable angina pectoris | 15 participants |
| Dronedarone | Overview of Cardiovascular Events | Systemic arterial embolism | 1 participants |
| Dronedarone | Overview of Cardiovascular Events | - MI | 3 participants |
| Dronedarone | Overview of Cardiovascular Events | - Hospitalization due to heart failure | 43 participants |
| Dronedarone | Overview of Cardiovascular Events | Stroke | 23 participants |
| Dronedarone | Overview of Cardiovascular Events | Episode of heart failure | 115 participants |
| Dronedarone | Overview of Cardiovascular Events | - Ischemic stroke | 18 participants |