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Primary Objective:
To identify the optimal interval to restart oral anticoagulation after traumatic intracranial hemorrhage that will minimize thrombotic events and major bleeding by performing a response adaptive randomized (RAR) PROBE clinical trial of restarting in anticoagulant-associated traumatic intracranial hemorrhage patients, comparing restart at 1 week to restart at 2 weeks or at 4 weeks, with a primary composite outcome of major thrombotic events and bleeding.
Primary Outcome: 60-day composite of thromboembolic events, defined as DVT, pulmonary emboli, myocardial infarctions, ischemic strokes and systemic emboli, and bleeding events defined as non-CNS major bleeding events (modified BARC3 or above) and worsening index tICrH or new intracranial hemorrhage (ICrH).
Secondary objectives of this trial include:
Full description
Title: Restart tICrH Protocol Synopsis A Prospective Randomized Open Label Blinded Endpoint Response Adaptive Clinical Trial of Timing to Restart Direct Oral Anticoagulants After Traumatic Intracranial Hemorrhage
Objectives: To identify the optimal interval to restart oral anticoagulation after traumatic intracranial hemorrhage that will minimize thrombotic events and major bleeding by performing a response adaptive randomized (RAR) clinical trial of restarting in anticoagulant-associated traumatic intracranial hemorrhage patients, comparing restart at 1 week to restart at 2 weeks or at 4 weeks, with a primary composite outcome of major thrombotic events and bleeding.
Hypotheses: We hypothesize that restarting an oral anticoagulant at one week after anticoagulant-associated traumatic intracranial hemorrhage, compared to delayed restarting, reduces a composite outcome of major thrombotic events and major bleeding.
Study design Prospective, response adaptive randomized, open-label, blinded end-point (PROBE), 40 center national trial Study population -- Approximately 1100 participants with traumatic intracranial hemorrhage and an indication for Direct Oral Anticoagulant Main inclusion criteria
Main exclusion criteria
Interventions: • The trial will randomize patients with anticoagulant-associated traumatic intracranial hemorrhage to restart DOAC at 1 week or 2 weeks or 4 weeks, using an adaptive randomization algorithm that increases the probability of patients being randomized to treatment arms with lower event rates.
Primary efficacy outcome: A 60-day composite outcome that includes the following clinical events:
A. Bleeding Events Worsening tICrH/new ICrH
1)Hematoma expansion/new ICrH lesion on imaging 2)causing objective change in clinical status and 3)leading to stop of anticoagulation (must include all three).
Extracranial Major bleeding BARC3a or above definition. B. Thrombotic events Venous Thromboembolism (VTE) It is defined as a clinical diagnosis of acute proximal (popliteal and above) deep vein thrombosis or pulmonary embolus confirmed on imaging (compression ultrasound or venogram for DVT, CT angiography, other angiography or ventilation/perfusion scan for PE) by a radiologist qualified to interpret the scans in a timely manner. If the radiologist cannot or does not attest to acute versus chronic thrombus, the Adjudication Committee will make this determination according to its charter.
Myocardial Infarction (MI) Fourth Universal Definition of Myocardial Infarction.
Stroke New focal neurologic deficit consistent with ischemic stroke and confirmed by a stroke specialist or brain imaging. Brain imaging must be performed but need not be positive if the stroke specialist (neurology, neurosurgery or internal medicine) deems a clinically probable stroke.
Systemic Embolism A clinical diagnosis of extracranial infarction associated with likely thromboembolism and documented by angiography or surgery in the absence of atherosclerotic occlusion.
Cardiovascular death non bleeding Death resulting from an acute myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, death due to cardiovascular procedures, and death from other cardiovascular causes 45. A patient who has both this outcome and another thrombotic outcome will only be counted once as this outcome.
Secondary outcomes: Modified Rankin Scale and Disability Rating Scale
Safety outcomes: Incorporated in composite as thrombotic and bleeding events
Statistical analysis: All interim and final analyses will be conducted on the primary outcome, the composite 60-day outcome of thromboembolic events and recurrent hemorrhage. Both thrombotic and bleeding outcomes will be modeled as a function of the three treatment arms in a dose (time)/response (events composite) model. Two Bernoulli models will be used to estimate thromboembolism and recurrent hemorrhage. Each of the rates for the Bernoulli values by dose are θd and δd for thromboembolism and recurrent hemorrhage respectively. These rates are combined to provide a utility function Ud=-θd-δd, so higher values of Ud correspond to the better dose to establish specifically whether at a week is best and generally whether earlier is better than later.
Sample size: 1100
Clinical sites: Approximately 40 trauma center clinical sites in the US.
Recruitment period: Approximately 60 months
Follow-up period: Participants will be followed weekly for 60 days, the study end date.
Special procedures: N/A
Coordinating centers: Seton Dell Medical School Stroke Institute, Coalition for National Trauma Research, Kansas University Medical Center
Sponsor: Seton Dell Medical School Stroke Institute
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Inclusion criteria
Entry into the trial is primarily driven pragmatically by clinician intent to restart a Direct Oral Anticoagulant (DOAC) after anticoagulant-associated traumatic intracranial hemorrhage and equipoise concerning restart of anticoagulation at the specified time intervals. DOAC will be at label dose with label adjustments for creatinine clearance. DOAC will be at continuation dose, i.e. not initial therapy high doses in the setting of VTE.
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1,100 participants in 3 patient groups
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Central trial contact
Truman J Milling, MD; Patrick Lawrence
Data sourced from clinicaltrials.gov
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