Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE (RE-SONATE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00558259
First received: November 13, 2007
Last updated: February 24, 2014
Last verified: February 2014
Results First Received: January 31, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double-Blind;   Primary Purpose: Prevention
Condition: Venous Thromboembolism
Interventions: Drug: dabigatran etexilate 150 mg twice daily (BID)
Drug: matching placebo twice daily (BID)

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
There were 3 patients randomised to placebo who received Dabigatran only. For all analyses of efficacy, these patients are analysed as randomised. For all analyses of safety, these patients are analysed as treated.

Reporting Groups
  Description
Dabigatran Dabigatran 150mg bid (twice daily)
Placebo Matching placebo

Participant Flow:   Overall Study
    Dabigatran     Placebo  
STARTED     681 [1]   662 [2]
COMPLETED     610 [3]   563 [3]
NOT COMPLETED     71     99  
Adverse Event                 50                 81  
Protocol Violation                 9                 5  
Withdrawal by Subject                 12                 13  
[1] Number who started treatment. There were 4 patients randomised to Dabigatran and not treated.
[2] Number who started treatment. There were 6 patients randomised to placebo and not treated.
[3] Completed treatment.



  Baseline Characteristics
  Hide 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.
No text entered.

Reporting Groups
  Description
Dabigatran Dabigatran 150mg bid
Placebo Matching placebo
Total Total of all reporting groups

Baseline Measures
    Dabigatran     Placebo     Total  
Number of Participants  
[units: participants]
  681     662     1343  
Age  
[units: Years]
Mean ± Standard Deviation
  56.1  ± 15.5     55.5  ± 15.1     55.8  ± 15.3  
Gender  
[units: Participants]
     
Female     300     298     598  
Male     381     364     745  
Body mass index (BMI) continuous  
[units: kg/m^2]
Mean ± Standard Deviation
  28.45  ± 5.44     28.41  ± 5.56     28.43  ± 5.50  



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Including Unexplained Death During the Intended Treatment Period   [ Time Frame: 6 months ]

Measure Type Primary
Measure Title Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Including Unexplained Death During the Intended Treatment Period
Measure Description Symptomatic recurrent VTE is the composite of recurrent deep vein thrombosis (DVT) , fatal or non-fatal pulmonary embolism (PE). Whilst the endpoint is time to event, the measured values present the number of participant with event and the hazard ratio presents the time to event.
Time Frame 6 months  
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 (FAS) and analysed as randomised. FAS is defined as randomised and treated.

Reporting Groups
  Description
Dabigatran Dabigatran 150mg bid
Placebo Matching placebo

Measured Values
    Dabigatran     Placebo  
Number of Participants Analyzed  
[units: participants]
  681     662  
Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Including Unexplained Death During the Intended Treatment Period  
[units: Participants]
  3     37  


Statistical Analysis 1 for Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Including Unexplained Death During the Intended Treatment Period
Groups [1] All groups
Method [2] Regression, Cox
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.08
Standard Error of the mean ± 0.05
95% Confidence Interval ( 0.02 to 0.25 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Dabigatran vs placebo
[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:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



2.  Secondary:   Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Excluding Unexplained Death During the Intended Treatment Period   [ Time Frame: 6 months ]

Measure Type Secondary
Measure Title Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Excluding Unexplained Death During the Intended Treatment Period
Measure Description Symptomatic recurrent VTE is the composite of recurrent deep vein thrombosis (DVT) , fatal or non-fatal pulmonary embolism (PE). Whilst the endpoint is time to event, the measured values present the number of participant with event and the hazard ratio presents the time to event.
Time Frame 6 months  
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.
FAS and analysed as randomised.

Reporting Groups
  Description
Dabigatran Dabigatran 150mg bid
Placebo Matching placebo

Measured Values
    Dabigatran     Placebo  
Number of Participants Analyzed  
[units: participants]
  681     662  
Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Excluding Unexplained Death During the Intended Treatment Period  
[units: Participants]
  3     35  


Statistical Analysis 1 for Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Excluding Unexplained Death During the Intended Treatment Period
Groups [1] All groups
Method [2] Regression, Cox
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.08
Standard Error of the mean ± 0.05
95% Confidence Interval ( 0.03 to 0.27 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Dabigatran vs placebo
[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:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



3.  Secondary:   Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period   [ Time Frame: 6 months ]

Measure Type Secondary
Measure Title Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period
Measure Description Number of the participants with centrally confirmed symptomatic recurrent deep venous thrombotic (DVT) events during the intended treatment period were described.
Time Frame 6 months  
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.
FAS and analysed as randomised.

Reporting Groups
  Description
Dabigatran Dabigatran 150mg bid
Placebo Matching placebo

Measured Values
    Dabigatran     Placebo  
Number of Participants Analyzed  
[units: participants]
  681     662  
Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period  
[units: Participants]
  2     23  


Statistical Analysis 1 for Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period
Groups [1] All groups
Method [2] Fisher Exact
P Value [3] < 0.0001
[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:
  No text entered.

Statistical Analysis 2 for Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period
Groups [1] Dabigatran
Percentage of participants with events [2] 0.3
95% Confidence Interval ( 0.04 to 1.06 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  The confidence interval (Clopper-Pearson method) was calculated for the percentage of participants experiencing DVT in Dabigatran group.

Statistical Analysis 3 for Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period
Groups [1] Placebo
Percentage of participants with events [2] 3.5
95% Confidence Interval ( 2.21 to 5.17 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  The confidence interval (Clopper-Pearson method) was calculated for the percentage of participants experiencing DVT in placebo group.



4.  Secondary:   Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period   [ Time Frame: 6 months ]

Measure Type Secondary
Measure Title Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period
Measure Description Number of participants with centrally confirmed symptomatic pulmonary embolism (PE) events during the intended treatment period were described.
Time Frame 6 months  
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.
FAS and analysed as randomised.

Reporting Groups
  Description
Dabigatran Dabigatran 150mg bid
Placebo Matching placebo

Measured Values
    Dabigatran     Placebo  
Number of Participants Analyzed  
[units: participants]
  681     662  
Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period  
[units: Participants]
  1     14  


Statistical Analysis 1 for Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period
Groups [1] All groups
Method [2] Fisher Exact
P Value [3] 0.0004
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Dabigatran vs. Placebo
[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:
  No text entered.

Statistical Analysis 2 for Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period
Groups [1] Dabigatran
Percentage of participants with events [2] 0.1
95% Confidence Interval ( 0.00 to 0.82 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  The confidence interval (Clopper-Pearson method) was calculated for the percentage of participants experiencing PE in Dabigatran group.

Statistical Analysis 3 for Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period
Groups [1] Placebo
Percentage of participants with events [2] 2.1
95% Confidence Interval ( 1.16 to 3.52 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  The confidence interval (Clopper-Pearson method) was calculated for the percentage of participants experiencing PE in placebo group.



5.  Secondary:   Centrally Confirmed Unexplained Deaths During the Intended Treatment Period   [ Time Frame: 6 months ]

Measure Type Secondary
Measure Title Centrally Confirmed Unexplained Deaths During the Intended Treatment Period
Measure Description Number of participants with centrally confirmed unexplained deaths during the intended treatment period were described.
Time Frame 6 months  
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.
FAS and analysed as randomised.

Reporting Groups
  Description
Dabigatran Dabigatran 150mg bid
Placebo Matching placebo

Measured Values
    Dabigatran     Placebo  
Number of Participants Analyzed  
[units: participants]
  681     662  
Centrally Confirmed Unexplained Deaths During the Intended Treatment Period  
[units: participants]
  0     2  


Statistical Analysis 1 for Centrally Confirmed Unexplained Deaths During the Intended Treatment Period
Groups [1] All groups
Method [2] Fisher Exact
P Value [3] 0.2428
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Dabigatran vs. Placebo
[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:
  No text entered.

Statistical Analysis 2 for Centrally Confirmed Unexplained Deaths During the Intended Treatment Period
Groups [1] Dabigatran
Percentage of participants with events [2] 0.0
95% Confidence Interval ( 0.00 to 0.54 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  The confidence interval (Clopper-Pearson method) was calculated for the percentage of participants with unexplained death in Dabigatran group.

Statistical Analysis 3 for Centrally Confirmed Unexplained Deaths During the Intended Treatment Period
Groups [1] Placebo
Percentage of participants with events [2] 0.3
95% Confidence Interval ( 0.04 to 1.09 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  The confidence interval (Clopper-Pearson method) was calculated for the percentage of participants with unexplained death in placebo group.



6.  Secondary:   Centrally Confirmed Bleeding Event During the Treatment Period   [ Time Frame: 6 months ]

Measure Type Secondary
Measure Title Centrally Confirmed Bleeding Event During the Treatment Period
Measure Description

Major bleeding events (MBE) had to fulfil at least 1 of the following criteria:

  • Fatal bleeding
  • Associated with a fall in haemoglobin of ≥2 g/dL
  • Led to the transfusion of ≥2 units packed cells or whole blood
  • Occurred in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal

Other clinically relevant bleeding was defined as overt bleeding not meeting the criteria for an MBE but associated with medical intervention, unscheduled contact with a physician, (temporary) cessation of study treatment, or associated with discomfort such as pain, or impairment of activities of daily life.

Examples of these bleedings were:

  • Bleeding that compromised haemodynamics
  • Bleeding that led to hospitalisation

Trivial bleeding events were defined as all other bleeding events that did not fulfil the criteria of MBEs or CRBEs.

All bleeding events include MBEs, CRBEs, and trivial bleeding events.

Time Frame 6 months  
Safety Issue Yes  

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.
FAS and analysed as treated. There were 3 participants who were randomised to placebo but treated with dabigatran only.

Reporting Groups
  Description
Dabigatran Dabigatran 150mg bid
Placebo Matching placebo

Measured Values
    Dabigatran     Placebo  
Number of Participants Analyzed  
[units: participants]
  684     659  
Centrally Confirmed Bleeding Event During the Treatment Period  
[units: participants]
   
MBE     2     0  
MBE or CRBE     36     12  
All Bleeding     72     39  


Statistical Analysis 1 for Centrally Confirmed Bleeding Event During the Treatment Period
Groups [1] All groups
Method [2] Fisher Exact
P Value [3] 0.4998
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Dabigatran vs. Placebo - Analysis of time to first occurrence of an MBE during the treatment period - FAS - as treated.
[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:
  As the Cox model did not converge due to too few events, hazard ratios are not estimable.

Statistical Analysis 2 for Centrally Confirmed Bleeding Event During the Treatment Period
Groups [1] Dabigatran
Percentage of participants with events [2] 0.3
95% Confidence Interval ( 0.04 to 1.05 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  The confidence interval (Clopper-Pearson method) was calculated for the percentage of participants experiencing MBE in Dabigatran group.

Statistical Analysis 3 for Centrally Confirmed Bleeding Event During the Treatment Period
Groups [1] Placebo
Percentage of participants with events [2] 0.0
95% Confidence Interval ( 0.00 to 0.56 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  The confidence interval (Clopper-Pearson method) was calculated for the percentage of participants experiencing MBE in placebo group.

Statistical Analysis 4 for Centrally Confirmed Bleeding Event During the Treatment Period
Groups [1] All groups
Method [2] Regression, Cox
P Value [3] 0.0013
Hazard Ratio (HR) [4] 2.92
Standard Error of the mean ± 0.97
95% Confidence Interval ( 1.52 to 5.60 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Dabigatran vs. Placebo- Analysis of time to first occurrence of a MBE or CRBE during the treatment period - FAS - as treated.
[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:
  No text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Centrally Confirmed Bleeding Event During the Treatment Period
Groups [1] All groups
Method [2] Regression, Cox
P Value [3] 0.0027
Hazard Ratio (HR) [4] 1.82
Standard Error of the mean ± 0.36
95% Confidence Interval ( 1.23 to 2.68 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Dabigatran vs. Placebo- Analysis of time to first occurrence of any bleeding event during the treatment period - FAS - as treated
[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:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



7.  Secondary:   Centrally Confirmed Cardiovascular Events During the Treatment Period   [ Time Frame: 6 months ]

Measure Type Secondary
Measure Title Centrally Confirmed Cardiovascular Events During the Treatment Period
Measure Description Cardiovascular events that occurred during the treatment period + 3 days were summarised by treatment groups.
Time Frame 6 months  
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.
FAS and analysed as treated. There were 3 participants who were randomised to placebo but treated with dabigatran only.

Reporting Groups
  Description
Dabigatran Dabigatran 150mg bid
Placebo Matching placebo

Measured Values
    Dabigatran     Placebo  
Number of Participants Analyzed  
[units: participants]
  684     659  
Centrally Confirmed Cardiovascular Events During the Treatment Period  
[units: participants]
  3     2  

No statistical analysis provided for Centrally Confirmed Cardiovascular Events During the Treatment Period



8.  Secondary:   Laboratory Measures, Especially Liver Function Tests (LFTs)   [ Time Frame: 6 months ]

Measure Type Secondary
Measure Title Laboratory Measures, Especially Liver Function Tests (LFTs)
Measure Description Number of participants with possible clinically significant abnormalities during the treatment period.
Time Frame 6 months  
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.
FAS − As Treated Assignment

Reporting Groups
  Description
Dabigatran Dabigatran 150mg bid
Placebo Matching placebo

Measured Values
    Dabigatran     Placebo  
Number of Participants Analyzed  
[units: participants]
  684     659  
Laboratory Measures, Especially Liver Function Tests (LFTs)  
[units: participants]
   
AST increase (N=655, 629)     2     2  
ALT increase (N=655, 629)     3     5  
Alkaline phosphatase increase (N=658, 629)     0     0  
Total bilirubin increase (N=658, 628)     1     1  

No statistical analysis provided for Laboratory Measures, Especially Liver Function Tests (LFTs)




  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: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
phone: 1-800-243-0127
e-mail: clintriage.rdg@boehringer-ingelheim.com


No publications provided by Boehringer Ingelheim

Publications automatically indexed to this study:

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00558259     History of Changes
Other Study ID Numbers: 1160.63, 2007-002586-12
Study First Received: November 13, 2007
Results First Received: January 31, 2012
Last Updated: February 24, 2014
Health Authority: Australia: Dept of Health and Ageing Therapeutic Goods Admin
Austria: Federal Office for Safety in Health Care
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Canada: Health Canada
Czech Republic: State Institute for Drug Control (SUKL), CZ-100 41 Prague 10
Estonia: State Agency of Medicines, EE-5041Tartu
Germany: BfArM-Federal Authorities for Drugs and Medical Devices
Italy: Comitato di Bioetica dell'Azienda Ospedaliero-Universitaria Policlinico "Giaccone" di Palermo
Korea, Republic of: Korea Drug and Food Administration
Latvia: State Agency of Medicines, LV-1003 Riga
Lithuania: State Medicines Control Agency, LT-01132 Vilnius
Netherlands: Central Committee on Research Involving Human Subjects (CCMO)
New Zealand: Multicentre Ethics Committee/Medsafe
Poland: Registration Medicinal Product Medical Device Biocidal Product
Russia: Pharmacological Committee, Ministry of Health
Singapore: Health Sciences Authority,Ministry of Health
South Africa: Medicines Control Council
Sweden: Medical Products Agency Regional Ethics Committee of Gothenburg
Switzerland: Swissmedic Schweizerisches Heilmittelinstitut (Swiss Agency for Therapeutic Products
Thailand: Ministry of Public Health
United States: Food and Drug Administration