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Efficacy & Safety of Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation (DIONYSOS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00489736
Recruitment Status : Completed
First Posted : June 21, 2007
Results First Posted : November 9, 2009
Last Update Posted : February 18, 2010
Sponsor:
Information provided by:
Sanofi

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Atrial Fibrillation
Interventions Drug: dronedarone (SR33589)
Drug: amiodarone
Enrollment 504
Recruitment Details Enrollment of patients started on June 12, 2007 and was completed on October 3, 2008. The study was conducted in 112 centers in 23 countries. Minimum duration of treatment was 6 months. Minimum duration of observation was last patient's randomization plus 190 days.
Pre-assignment Details Planned sample size was 472. Six hundred and eighteen patients (618) were screened of which 113 did not verify one or more selection criteria. One eligible patient received a placebo capsule (morning intake in the amiodarone group) but was not randomized in the trial. This patient did not report any adverse event and was excluded from all analyses.
Arm/Group Title Dronedarone 400mg Bid Amiodarone 600mg/200mg od
Hide Arm/Group Description dronedarone tablets 400mg twice daily (bid) amiodarone 600mg once daily (od) for 28 days, then amiodarone 200mg once daily (od)
Period Title: Overall Study
Started 249 [1] 255 [1]
Completed 153 [2] 186 [2]
Not Completed 96 69
Reason Not Completed
Lack of Efficacy             53             14
Adverse Event             32             45
Poor compliance             6             2
Not coded/ Not pre-specified             5             8
[1]
Randomized and treated patients
[2]
completed study drug period
Arm/Group Title Dronedarone 400mg Bid Amiodarone 600mg/200mg od Total
Hide Arm/Group Description dronedarone tablets 400mg twice daily (bid) amiodarone 600mg once daily (od) for 28 days, then amiodarone 200mg once daily (od) Total of all reporting groups
Overall Number of Baseline Participants 249 255 504
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 249 participants 255 participants 504 participants
18 to < 65 years 125 138 263
65 to < 75 years 76 70 146
>= 75 years 48 47 95
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 249 participants 255 participants 504 participants
64.4  (10.8) 63.7  (10.6) 64.0  (10.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 249 participants 255 participants 504 participants
Female
73
  29.3%
73
  28.6%
146
  29.0%
Male
176
  70.7%
182
  71.4%
358
  71.0%
1.Primary Outcome
Title Treatment Failure
Hide Description The primary event is the treatment failure defined as the first recurrence of atrial fibrillation or premature study drug discontinuation for intolerance or lack of efficacy according to the investigator judgement. The primary efficacy analysis is performed on the time from first study drug intake 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 study duration is 6 months (+10 days); maximum is 15 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized and treated patients (receiving at least one dose of study drug) were included in the efficacy analysis according to the treatment received.
Arm/Group Title Dronedarone 400mg Bid Amiodarone 600mg/200mg od
Hide Arm/Group Description:
dronedarone tablets 400mg twice daily (bid)
amiodarone 600mg once daily (od) for 28 days, then amiodarone 200mg once daily (od)
Overall Number of Participants Analyzed 249 255
Measure Type: Number
Unit of Measure: participants
184 141
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dronedarone 400mg Bid, Amiodarone 600mg/200mg od
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Cumulative incidence functions in each treatment group were calculated using time-to-event non-parametric Kaplan-Meier estimate. The primary comparison was performed at the 5% level using a 2-sided Log rank test.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.59
Confidence Interval 95%
1.28 to 1.98
Estimation Comments The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It provides the relative hazard of treatment failure for the dronedarone group compared with the amiodarone group.
2.Secondary Outcome
Title Occurrence of the Main Safety Endpoint (MSE) Defined as Thyroid, Hepatic, Pulmonary, Neurological, Skin, Eye, or Gastrointestinal Specific Treatment Emergent Events or Premature Study Drug Discontinuation Following Any Adverse Event
Hide Description The considered event is the occurrence of the MSE defined as thyroid, hepatic, pulmonary, neurological, skin, eye, or gastrointestinal specific treatment emergent events or premature study drug discontinuation following any adverse event (AE), whichever comes first. The analysis is performed on the time from first study drug intake 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 study duration is 6 months (+10 days); maximum is 15 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized and treated patients (receiving at least one dose of study drug) were included in the safety analysis according to the treatment received.
Arm/Group Title Dronedarone 400mg Bid Amiodarone 600mg/200mg od
Hide Arm/Group Description:
dronedarone tablets 400mg twice daily (bid)
amiodarone 600mg once daily (od) for 28 days, then amiodarone 200mg once daily (od)
Overall Number of Participants Analyzed 249 255
Measure Type: Number
Unit of Measure: participants
83 107
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dronedarone 400mg Bid, Amiodarone 600mg/200mg od
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.13
Comments Cumulative incidence functions in each treatment group were calculated using time-to-event non-parametric Kaplan-Meier estimate. The comparison was performed at the 5% level using a 2-sided Log rank test.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval 95%
0.60 to 1.07
Estimation Comments The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It provides the relative hazard of main safety event occurrence for the dronedarone group compared with the amiodarone group.
3.Other Pre-specified Outcome
Title Occurrence of the MSE Excluding Gastrointestinal Specific Treatment Emergent Events Defined as Diarrhoea, Nausea, Vomiting
Hide Description The considered event is the occurrence of the MSE excluding gastrointestinal specific treatment emergent events defined as diarrhoea, nausea, vomiting. The analysis is performed on the time from first study drug intake 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 study duration is 6 months (+10 days); maximum is 15 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized and treated patients (receiving at least one dose of study drug) were included in the safety analysis according to the treatment received.
Arm/Group Title Dronedarone 400mg Bid Amiodarone 600mg/200mg od
Hide Arm/Group Description:
dronedarone tablets 400mg twice daily (bid)
amiodarone 600mg once daily (od) for 28 days, then amiodarone 200mg once daily (od)
Overall Number of Participants Analyzed 249 255
Measure Type: Number
Unit of Measure: participants
61 99
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dronedarone 400mg Bid, Amiodarone 600mg/200mg od
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments Cumulative incidence functions in each treatment group were calculated using time-to-event non-parametric Kaplan-Meier estimate. The comparison was performed at the 5% level using a 2-sided Log rank test.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.61
Confidence Interval 95%
0.44 to 0.84
Estimation Comments The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It provides the relative hazard of MSE occurrence excluding gastrointestinal events, for the dronedarone group compared with the amiodarone group.
Time Frame From first to last study drug intake +10 days i.e. end of the study.
Adverse Event Reporting Description The safety population was the "All randomized and treated patients" population.
 
Arm/Group Title Dronedarone 400mg Bid Amiodarone 600mg/200mg od
Hide Arm/Group Description dronedarone tablets 400mg twice daily (bid) amiodarone 600mg once daily (od) for 28 days, then amiodarone 200mg once daily (od)
All-Cause Mortality
Dronedarone 400mg Bid Amiodarone 600mg/200mg od
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Dronedarone 400mg Bid Amiodarone 600mg/200mg od
Affected / at Risk (%) Affected / at Risk (%)
Total   34/249 (13.65%)   37/255 (14.51%) 
Blood and lymphatic system disorders     
Anaemia * 1  1/249 (0.40%)  0/255 (0.00%) 
Hypoprothrombinaemia * 1  0/249 (0.00%)  1/255 (0.39%) 
Cardiac disorders     
Cardiac failure * 1  6/249 (2.41%)  1/255 (0.39%) 
Cardiac failure congestive * 1  1/249 (0.40%)  6/255 (2.35%) 
Bradycardia * 1  1/249 (0.40%)  2/255 (0.78%) 
Angina pectoris * 1  1/249 (0.40%)  1/255 (0.39%) 
Arteriosclerosis coronary artery * 1  1/249 (0.40%)  0/255 (0.00%) 
Diastolic dysfunction * 1  1/249 (0.40%)  0/255 (0.00%) 
Left ventricular dysfunction * 1  1/249 (0.40%)  0/255 (0.00%) 
Pericarditis * 1  1/249 (0.40%)  0/255 (0.00%) 
Acute coronary syndrome * 1  0/249 (0.00%)  1/255 (0.39%) 
Acute myocardial infarction * 1  0/249 (0.00%)  1/255 (0.39%) 
Atrioventricular block second degree * 1  0/249 (0.00%)  1/255 (0.39%) 
Coronary artery stenosis * 1  0/249 (0.00%)  1/255 (0.39%) 
Sick sinus syndrome * 1  0/249 (0.00%)  1/255 (0.39%) 
Sinus bradycardia * 1  0/249 (0.00%)  1/255 (0.39%) 
Gastrointestinal disorders     
Duodenal ulcer * 1  1/249 (0.40%)  0/255 (0.00%) 
Gastric haemorrhage * 1  1/249 (0.40%)  0/255 (0.00%) 
Inguinal hernia * 1  1/249 (0.40%)  0/255 (0.00%) 
Gastrointestinal haemorrhage * 1  0/249 (0.00%)  1/255 (0.39%) 
Gastrointestinal necrosis * 1  0/249 (0.00%)  1/255 (0.39%) 
General disorders     
Death * 1  1/249 (0.40%)  0/255 (0.00%) 
Oedema peripheral * 1  1/249 (0.40%)  0/255 (0.00%) 
Chest pain * 1  0/249 (0.00%)  1/255 (0.39%) 
Sudden death * 1  0/249 (0.00%)  1/255 (0.39%) 
Hepatobiliary disorders     
Hepatocellular injury * 1  1/249 (0.40%)  0/255 (0.00%) 
Mixed liver injury * 1  1/249 (0.40%)  0/255 (0.00%) 
Cholangitis * 1  0/249 (0.00%)  1/255 (0.39%) 
Cholecystitis acute * 1  0/249 (0.00%)  1/255 (0.39%) 
Infections and infestations     
Pneumonia * 1  2/249 (0.80%)  0/255 (0.00%) 
Diverticulitis * 1  1/249 (0.40%)  1/255 (0.39%) 
Bronchitis * 1  0/249 (0.00%)  2/255 (0.78%) 
Cellulitis * 1  0/249 (0.00%)  1/255 (0.39%) 
Ear infection * 1  0/249 (0.00%)  1/255 (0.39%) 
Escherichia sepsis * 1  0/249 (0.00%)  1/255 (0.39%) 
Gastroenteritis * 1  0/249 (0.00%)  1/255 (0.39%) 
Oesophageal candidiasis * 1  0/249 (0.00%)  1/255 (0.39%) 
Septic shock * 1  0/249 (0.00%)  1/255 (0.39%) 
Injury, poisoning and procedural complications     
Therapeutic agent toxicity * 1  1/249 (0.40%)  3/255 (1.18%) 
Post procedural haemorrhage * 1  1/249 (0.40%)  0/255 (0.00%) 
Accidental overdose * 1  0/249 (0.00%)  2/255 (0.78%) 
Thoracic vertebral fracture * 1  0/249 (0.00%)  1/255 (0.39%) 
Investigations     
Blood creatinine increased * 1  1/249 (0.40%)  1/255 (0.39%) 
Electrocardiogram PR prolongation * 1  1/249 (0.40%)  0/255 (0.00%) 
International normalised ratio increased * 1  0/249 (0.00%)  2/255 (0.78%) 
Metabolism and nutrition disorders     
Diabetic foot * 1  1/249 (0.40%)  0/255 (0.00%) 
Hypoglycaemia * 1  1/249 (0.40%)  0/255 (0.00%) 
Hyperkalaemia * 1  0/249 (0.00%)  1/255 (0.39%) 
Hyponatraemia * 1  0/249 (0.00%)  1/255 (0.39%) 
Musculoskeletal and connective tissue disorders     
Symphysiolysis * 1  1/249 (0.40%)  0/255 (0.00%) 
Muscle haemorrhage * 1  0/249 (0.00%)  1/255 (0.39%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung squamous cell carcinoma stage unspecified * 1  1/249 (0.40%)  1/255 (0.39%) 
Anaplastic thyroid cancer * 1  1/249 (0.40%)  0/255 (0.00%) 
Bladder cancer * 1  1/249 (0.40%)  0/255 (0.00%) 
Carcinoma in situ of bladder * 1  1/249 (0.40%)  0/255 (0.00%) 
Adrenal adenoma * 1  0/249 (0.00%)  1/255 (0.39%) 
Gastrointestinal stromal tumour * 1  0/249 (0.00%)  1/255 (0.39%) 
Lung cancer metastatic * 1  0/249 (0.00%)  1/255 (0.39%) 
Small cell lung cancer stage unspecified * 1  0/249 (0.00%)  1/255 (0.39%) 
Nervous system disorders     
Cerebral ischaemia * 1  1/249 (0.40%)  0/255 (0.00%) 
Cerebrovascular accident * 1  1/249 (0.40%)  0/255 (0.00%) 
Ischaemic stroke * 1  1/249 (0.40%)  0/255 (0.00%) 
Syncope * 1  0/249 (0.00%)  2/255 (0.78%) 
Haemorrhage intracranial * 1  0/249 (0.00%)  1/255 (0.39%) 
Renal and urinary disorders     
Haematuria * 1  1/249 (0.40%)  0/255 (0.00%) 
Urinary retention * 1  0/249 (0.00%)  1/255 (0.39%) 
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema * 1  1/249 (0.40%)  0/255 (0.00%) 
Bronchitis chronic * 1  1/249 (0.40%)  0/255 (0.00%) 
Dyspnoea * 1  1/249 (0.40%)  0/255 (0.00%) 
Pneumonitis * 1  1/249 (0.40%)  0/255 (0.00%) 
Pulmonary embolism * 1  1/249 (0.40%)  0/255 (0.00%) 
Hypoxia * 1  0/249 (0.00%)  1/255 (0.39%) 
Skin and subcutaneous tissue disorders     
Dermatitis allergic * 1  0/249 (0.00%)  1/255 (0.39%) 
Vascular disorders     
Pelvic venous thrombosis * 1  0/249 (0.00%)  1/255 (0.39%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 11.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Dronedarone 400mg Bid Amiodarone 600mg/200mg od
Affected / at Risk (%) Affected / at Risk (%)
Total   146/249 (58.63%)   165/255 (64.71%) 
Cardiac disorders     
Any Cardiac disorders * 1  21/249 (8.43%)  36/255 (14.12%) 
Bradycardia * 1  4/249 (1.61%)  14/255 (5.49%) 
Endocrine disorders     
Any Endocrine disorders * 1  3/249 (1.20%)  14/255 (5.49%) 
Eye disorders     
Any Eye disorders * 1  6/249 (2.41%)  13/255 (5.10%) 
Gastrointestinal disorders     
Any Gastrointestinal disorders * 1  54/249 (21.69%)  44/255 (17.25%) 
Diarrhoea * 1  23/249 (9.24%)  8/255 (3.14%) 
Nausea * 1  13/249 (5.22%)  9/255 (3.53%) 
General disorders     
Any General disorders and administration site conditions * 1  14/249 (5.62%)  26/255 (10.20%) 
Oedema peripheral * 1  6/249 (2.41%)  13/255 (5.10%) 
Infections and infestations     
Any Infections and infestations * 1  35/249 (14.06%)  35/255 (13.73%) 
Injury, poisoning and procedural complications     
Any Injury, poisoning and procedural complications * 1  8/249 (3.21%)  17/255 (6.67%) 
Investigations     
Any Investigations * 1  33/249 (13.25%)  35/255 (13.73%) 
Metabolism and nutrition disorders     
Any Metabolism and nutrition disorders * 1  8/249 (3.21%)  15/255 (5.88%) 
Musculoskeletal and connective tissue disorders     
Any Musculoskeletal and connective tissue disorders * 1  21/249 (8.43%)  22/255 (8.63%) 
Nervous system disorders     
Any Nervous system disorders * 1  17/249 (6.83%)  39/255 (15.29%) 
Dizziness * 1  8/249 (3.21%)  16/255 (6.27%) 
Psychiatric disorders     
Any Psychiatric disorders * 1  6/249 (2.41%)  23/255 (9.02%) 
Sleep disorder * 1  3/249 (1.20%)  19/255 (7.45%) 
Respiratory, thoracic and mediastinal disorders     
Any Respiratory, thoracic and mediastinal disorders * 1  21/249 (8.43%)  21/255 (8.24%) 
Skin and subcutaneous tissue disorders     
Any Skin and subcutaneous tissue disorders * 1  18/249 (7.23%)  23/255 (9.02%) 
Vascular disorders     
Any Vascular disorders * 1  9/249 (3.61%)  23/255 (9.02%) 
Hypertension * 1  7/249 (2.81%)  16/255 (6.27%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 11.0
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.
If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such publication for comment at least 45 days before any submission for publication. If requested by the Sponsor, any submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Results Point of Contact
Name/Title: International Clinical Development, Clinical Study Director
Organization: sanofi-aventis
Responsible Party: International Clinical Development, Clinical Study Director, sanofi-aventis
ClinicalTrials.gov Identifier: NCT00489736     History of Changes
Other Study ID Numbers: EFC4968
First Submitted: June 20, 2007
First Posted: June 21, 2007
Results First Submitted: September 30, 2009
Results First Posted: November 9, 2009
Last Update Posted: February 18, 2010