Venous Thromboembolism
Conditions
Brief summary
The primary efficacy objective is to evaluate whether dabigatran etexilate is superior to placebo in the long-term prevention of recurrent symptomatic venous thrombo-embolism (VTE) in patients with symptomatic deep-vein thrombosis (DVT) or pulmonary embolism (PE) who completed 6 to 18 months of treatment with vitamin K antagonist (VKA).
Interventions
DRUGdabigatran etexilate 150 mg twice daily (BID)
dabigatran etexilate capsules 150 mg BID
DRUGmatching placebo twice daily (BID)
Matching placebo BID
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with confirmed symptomatic PE or proximal DVT of the leg(s) who have been treated for 6 to 18 months with therapeutic dosages (intended INR between 2-3) of an oral VKA (e.g. warfarin, acenocoumarol, phenprocoumon, or fluindione) or RE-COVER study medication up to the moment of screening for the current study. 2. Written informed consent
Exclusion criteria
1. Younger then 18 years of age 2. Indication for VKA other than DVT and/or PE 3. Patients in whom anticoagulant treatment for their index PE or DVT should be continued 4. Active liver disease or liver disease decreasing survival (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or ALAT \> 3 x ULN 5. Creatinine clearance \< 30 ml/min 6. Acute bacterial endocarditis 7. Active bleeding or high risk for bleeding. 8. Uncontrolled hypertension (investigators judgement) 9. Intake of another experimental drug within the 30 days prior to randomization into the study 10. Life expectancy \<6 months 11. Childbearing potential without proper contraceptive measures\*, pregnancy or breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Including Unexplained Death During the Intended Treatment Period | 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period | 6 months | Number of the participants with centrally confirmed symptomatic recurrent deep venous thrombotic (DVT) events during the intended treatment period were described. |
| Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period | 6 months | Number of participants with centrally confirmed symptomatic pulmonary embolism (PE) events during the intended treatment period were described. |
| Centrally Confirmed Unexplained Deaths During the Intended Treatment Period | 6 months | Number of participants with centrally confirmed unexplained deaths during the intended treatment period were described. |
| Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Excluding Unexplained Death During the Intended Treatment Period | 6 months | 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. |
| Centrally Confirmed Cardiovascular Events During the Treatment Period | 6 months | Cardiovascular events that occurred during the treatment period + 3 days were summarised by treatment groups. |
| Laboratory Measures, Especially Liver Function Tests (LFTs) | 6 months | Number of participants with possible clinically significant abnormalities during the treatment period. |
| Centrally Confirmed Bleeding Event During the Treatment Period | 6 months | 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. |
Countries
Australia, Austria, Belgium, Canada, Czechia, Estonia, Germany, Italy, Latvia, Lithuania, Netherlands, New Zealand, Poland, Russia, Singapore, South Africa, South Korea, Sweden, Switzerland, Thailand, United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Dabigatran Dabigatran 150mg bid | 681 |
| Placebo Matching placebo | 662 |
| Total | 1,343 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 50 | 81 |
| Overall Study | Protocol Violation | 9 | 5 |
| Overall Study | Withdrawal by Subject | 12 | 13 |
Baseline characteristics
| Characteristic | Dabigatran | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 56.1 Years STANDARD_DEVIATION 15.5 | 55.5 Years STANDARD_DEVIATION 15.1 | 55.8 Years STANDARD_DEVIATION 15.3 |
| Body mass index (BMI) continuous | 28.45 kg/m^2 STANDARD_DEVIATION 5.44 | 28.41 kg/m^2 STANDARD_DEVIATION 5.56 | 28.43 kg/m^2 STANDARD_DEVIATION 5.5 |
| Sex: Female, Male Female | 300 Participants | 298 Participants | 598 Participants |
| Sex: Female, Male Male | 381 Participants | 364 Participants | 745 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 684 | 0 / 659 |
| serious Total, serious adverse events | 47 / 684 | 60 / 659 |
Outcome results
Primary
Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Including Unexplained Death During the Intended Treatment Period
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
Population: Full analysis set (FAS) and analysed as randomised. FAS is defined as randomised and treated.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Dabigatran | Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Including Unexplained Death During the Intended Treatment Period | 3 Participants | 0 |
| Placebo | Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Including Unexplained Death During the Intended Treatment Period | 37 Participants | 0 |
Comparison: Dabigatran vs placebop-value: <0.000195% CI: [0.02, 0.25]Regression, Cox
Secondary
Centrally Confirmed Bleeding Event During the Treatment Period
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
Population: FAS and analysed as treated. There were 3 participants who were randomised to placebo but treated with dabigatran only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabigatran | Centrally Confirmed Bleeding Event During the Treatment Period | MBE | 2 participants |
| Dabigatran | Centrally Confirmed Bleeding Event During the Treatment Period | MBE or CRBE | 36 participants |
| Dabigatran | Centrally Confirmed Bleeding Event During the Treatment Period | All Bleeding | 72 participants |
| Placebo | Centrally Confirmed Bleeding Event During the Treatment Period | MBE | 0 participants |
| Placebo | Centrally Confirmed Bleeding Event During the Treatment Period | MBE or CRBE | 12 participants |
| Placebo | Centrally Confirmed Bleeding Event During the Treatment Period | All Bleeding | 39 participants |
Comparison: Dabigatran vs. Placebo - Analysis of time to first occurrence of an MBE during the treatment period - FAS - as treated.p-value: 0.4998Fisher Exact
95% CI: [0.04, 1.05]
95% CI: [0, 0.56]
Comparison: Dabigatran vs. Placebo- Analysis of time to first occurrence of a MBE or CRBE during the treatment period - FAS - as treated.p-value: 0.001395% CI: [1.52, 5.6]Regression, Cox
Comparison: Dabigatran vs. Placebo- Analysis of time to first occurrence of any bleeding event during the treatment period - FAS - as treatedp-value: 0.002795% CI: [1.23, 2.68]Regression, Cox
Secondary
Centrally Confirmed Cardiovascular Events During the Treatment Period
Cardiovascular events that occurred during the treatment period + 3 days were summarised by treatment groups.
Time frame: 6 months
Population: FAS and analysed as treated. There were 3 participants who were randomised to placebo but treated with dabigatran only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran | Centrally Confirmed Cardiovascular Events During the Treatment Period | 3 participants |
| Placebo | Centrally Confirmed Cardiovascular Events During the Treatment Period | 2 participants |
Secondary
Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period
Number of participants with centrally confirmed symptomatic pulmonary embolism (PE) events during the intended treatment period were described.
Time frame: 6 months
Population: FAS and analysed as randomised.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran | Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period | 1 Participants |
| Placebo | Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period | 14 Participants |
Comparison: Dabigatran vs. Placebop-value: 0.0004Fisher Exact
95% CI: [0, 0.82]
95% CI: [1.16, 3.52]
Secondary
Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period
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
Population: FAS and analysed as randomised.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran | Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period | 2 Participants |
| Placebo | Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period | 23 Participants |
p-value: <0.0001Fisher Exact
95% CI: [0.04, 1.06]
95% CI: [2.21, 5.17]
Secondary
Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Excluding Unexplained Death During the Intended Treatment Period
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
Population: FAS and analysed as randomised.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran | Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Excluding Unexplained Death During the Intended Treatment Period | 3 Participants |
| Placebo | Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Excluding Unexplained Death During the Intended Treatment Period | 35 Participants |
Comparison: Dabigatran vs placebop-value: <0.000195% CI: [0.03, 0.27]Regression, Cox
Secondary
Centrally Confirmed Unexplained Deaths During the Intended Treatment Period
Number of participants with centrally confirmed unexplained deaths during the intended treatment period were described.
Time frame: 6 months
Population: FAS and analysed as randomised.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran | Centrally Confirmed Unexplained Deaths During the Intended Treatment Period | 0 participants |
| Placebo | Centrally Confirmed Unexplained Deaths During the Intended Treatment Period | 2 participants |
Comparison: Dabigatran vs. Placebop-value: 0.2428Fisher Exact
95% CI: [0, 0.54]
95% CI: [0.04, 1.09]
Secondary
Laboratory Measures, Especially Liver Function Tests (LFTs)
Number of participants with possible clinically significant abnormalities during the treatment period.
Time frame: 6 months
Population: FAS - As Treated Assignment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabigatran | Laboratory Measures, Especially Liver Function Tests (LFTs) | AST increase (N=655, 629) | 2 participants |
| Dabigatran | Laboratory Measures, Especially Liver Function Tests (LFTs) | ALT increase (N=655, 629) | 3 participants |
| Dabigatran | Laboratory Measures, Especially Liver Function Tests (LFTs) | Alkaline phosphatase increase (N=658, 629) | 0 participants |
| Dabigatran | Laboratory Measures, Especially Liver Function Tests (LFTs) | Total bilirubin increase (N=658, 628) | 1 participants |
| Placebo | Laboratory Measures, Especially Liver Function Tests (LFTs) | Total bilirubin increase (N=658, 628) | 1 participants |
| Placebo | Laboratory Measures, Especially Liver Function Tests (LFTs) | AST increase (N=655, 629) | 2 participants |
| Placebo | Laboratory Measures, Especially Liver Function Tests (LFTs) | Alkaline phosphatase increase (N=658, 629) | 0 participants |
| Placebo | Laboratory Measures, Especially Liver Function Tests (LFTs) | ALT increase (N=655, 629) | 5 participants |