Ignite Creation Date:
2024-05-06 @ 2:08 PM
Last Modification Date:
2024-10-26 @ 1:26 PM
Study NCT ID:
NCT04229758
Status:
NOT_YET_RECRUITING
Last Update Posted:
2021-05-19
First Post:
2020-01-13
Brief Title:
Restarting Anticoagulation After Traumatic Intracranial Hemorrhage
Sponsor:
University of Texas at Austin
Organization:
University of Texas at Austin
Study Overview
Official Title:
Restarting Anticoagulation After Traumatic Intracranial Hemorrhage Restart tICrH a Prospective Randomized Open Label Blinded Endpoint PROBE Pragmatic Time-dose Response Adaptive Clinical Trial
Status:
NOT_YET_RECRUITING
Status Verified Date:
2021-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Restart tICrH
Brief Summary:
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
1 To use the Trauma Quality Improvement Program TQIP of the American College of Surgeons - Committee on Trauma ACS-COT a well-established and highly respected trauma center oversight mechanism to translate findings of the trial into practice in a closed loop
2 To establish a relationship between time of restarting and overall secondary events ie a dose response that favors early restarting 1 week is better than 2 weeks and 2 weeks is better than 4 weeks
3 To explore patient centered utility weighting of thrombotic versus bleeding composite endpoint components by A 60-day Disability Rating Scale DRS 2425 and modified Rankin Scale mRS26 B Trial patient-reported standard gamble utilities including by race gender and ethnicity
4 To explore the composite without DVT in the thrombotic component
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
1 To use the Trauma Quality Improvement Program TQIP of the American College of Surgeons - Committee on Trauma ACS-COT a well-established and highly respected trauma center oversight mechanism to translate findings of the trial into practice in a closed loop
2 To establish a relationship between time of restarting and overall secondary events ie a dose response that favors early restarting 1 week is better than 2 weeks and 2 weeks is better than 4 weeks
3 To explore patient centered utility weighting of thrombotic versus bleeding composite endpoint components by A 60-day Disability Rating Scale DRS 2425 and modified Rankin Scale mRS26 B Trial patient-reported standard gamble utilities including by race gender and ethnicity
4 To explore the composite without DVT in the thrombotic component
Detailed 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
1 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
2 Acute traumatic intracranial hemorrhage on anticoagulation for Atrial Fibrillation AF or Venous Thromboembolism VTE
3 Patient is higher risk for stroke or other thrombotic events as witnessed by having a CHA2DS2-VASc score of 3
4 DOAC will be prescribed at label dose with label adjustments for creatinine clearance DOAC will be at continuation dose ie not initial therapy high doses in the setting of VTE
Main exclusion criteria
1 Mechanical ValveVentricular Assist Device excludes 1
2 SDH 8 mm maximum width or any midline shift at any time point or more than one SDH excludes 10
3 Physician plan to startrestart antiplatelet therapy during trial period excludes 5
4 Abbreviated Injury Scale other than head 3 excludes 10
5 Pregnancy excludes 0 median age 81 range 58-99
6 Inability to understand need for adherence to study protocol
7 Renal function below DOAC label exclusions
8 Any active pathological bleeding no acute blood most recent CT
9 Hypersensitivity to drug or other label contraindication
10 Any bleeding that the investigator deems unsafe to restart DOAC at 1 week post injury or conversely unsafe to hold DOAC to 4 weeks
11 Completion of DOAC therapy expected prior to 60-day primary endpoint eg 3-6-month VTE treatment
12 Concomitant strong inducersinhibitors of p-gp and CYP3A4
13 Low body weight 45kg
14 Inability to swallow
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 tICrHnew ICrH
1Hematoma expansionnew ICrH lesion on imaging 2causing objective change in clinical status and 3leading 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 ventilationperfusion 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 timeresponse 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 NA
Coordinating centers Seton Dell Medical School Stroke Institute Coalition for National Trauma Research Kansas University Medical Center
Sponsor Seton Dell Medical School Stroke Institute
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
1 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
2 Acute traumatic intracranial hemorrhage on anticoagulation for Atrial Fibrillation AF or Venous Thromboembolism VTE
3 Patient is higher risk for stroke or other thrombotic events as witnessed by having a CHA2DS2-VASc score of 3
4 DOAC will be prescribed at label dose with label adjustments for creatinine clearance DOAC will be at continuation dose ie not initial therapy high doses in the setting of VTE
Main exclusion criteria
1 Mechanical ValveVentricular Assist Device excludes 1
2 SDH 8 mm maximum width or any midline shift at any time point or more than one SDH excludes 10
3 Physician plan to startrestart antiplatelet therapy during trial period excludes 5
4 Abbreviated Injury Scale other than head 3 excludes 10
5 Pregnancy excludes 0 median age 81 range 58-99
6 Inability to understand need for adherence to study protocol
7 Renal function below DOAC label exclusions
8 Any active pathological bleeding no acute blood most recent CT
9 Hypersensitivity to drug or other label contraindication
10 Any bleeding that the investigator deems unsafe to restart DOAC at 1 week post injury or conversely unsafe to hold DOAC to 4 weeks
11 Completion of DOAC therapy expected prior to 60-day primary endpoint eg 3-6-month VTE treatment
12 Concomitant strong inducersinhibitors of p-gp and CYP3A4
13 Low body weight 45kg
14 Inability to swallow
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 tICrHnew ICrH
1Hematoma expansionnew ICrH lesion on imaging 2causing objective change in clinical status and 3leading 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 ventilationperfusion 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 timeresponse 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 NA
Coordinating centers Seton Dell Medical School Stroke Institute Coalition for National Trauma Research Kansas University Medical Center
Sponsor Seton Dell Medical School Stroke Institute
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None