Restarting Anticoagulation After Traumatic Intracranial Hemorrhage

NCT04229758 | Not Yet Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: 2020090035
• Study Type: interventional
• Target: 1,100
• Locations: 1 country
• Sites: 1

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. 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. 2.To establish a relationship between time of restarting and overall secondary events, i.e. a dose response, that favors early restarting (1 week is better than 2 weeks and 2 weeks is better than 4 weeks.
3. 3.To explore patient centered utility weighting of thrombotic versus bleeding composite endpoint components by: A) 60-day Disability Rating Scale (DRS) 24,25 and modified Rankin Scale (mRS)26; B) Trial patient-reported standard gamble utilities including by race, gender and ethnicity.
4. 4.To explore the composite without DVT in the thrombotic component

Conditions

Hemorrhage; Intracranial Hemorrhages; Bleeding; Trauma

Keywords

Anticoagulation; Anticoagulant; Anticoagulants; Restart; Delay; Hemorrhage; ICH; SAH; SDH; DOAC; NOAC; apixaban; rivaroxaban; edoxaban

Outcome Measures

Primary Outcomes (1)

• 60 Day Composite of Thrombotic and Bleeding Events

  Composite of Thrombotic events, defined as DVT, PE, MI, Ischemic Strokes, and systemic emboli, cardiovascular death along with bleeding events defined as non-CNS major bleeding, worsening index tICrH, or new intracranial hemorrhage.

  60 days following index bleeding event

Secondary Outcomes (3)

• 60 Day Disability Rating Scale (1-29 with 29 being worse)

  60 days following index bleeding event

• 60 Day Modified Rankin Scale (1-6 with 6 being worse)

  60 days following index bleeding event

• Standard Gamble Patient Reported utilities for endpoints

  pre-randomization and after endpoints

Study Arms (3)

1 week

EXPERIMENTAL

Time to delay the initiation of anticoagulation is determined at randomization. Patients will be randomized to initiate anticoagulation 1 week, 2 weeks, or 4 weeks following injury.

Drug: Anticoagulants

2 weeks

EXPERIMENTAL

Time to delay the initiation of anticoagulation is determined at randomization. Patients will be randomized to initiate anticoagulation 1 week, 2 weeks, or 4 weeks following injury.

Drug: Anticoagulants

4 weeks

EXPERIMENTAL

Time to delay the initiation of anticoagulation is determined at randomization. Patients will be randomized to initiate anticoagulation 1 week, 2 weeks, or 4 weeks following injury.

Drug: Anticoagulants

Interventions

Anticoagulants DRUG

DOAC for the prevention of thromboembolic events in patients with non-valvular AF or VTE.

1 week; 2 weeks; 4 weeks

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Acute traumatic intracranial hemorrhage on anticoagulation for Atrial Fibrillation (AF) or Venous Thromboembolism (VTE) or both (2,500 patients per year at our 40 sites)
• Patient is higher risk for stroke or other thrombotic events as witnessed by having a CHA2DS2-VASc score of \> 3 (at least 3 of the following risk factors: age greater than 65,( age \> 75 counts for two points), history of stroke or TIA, history of heart failure, history of diabetes, history of atherosclerotic vascular disease, female gender, history of hypertension) (Excludes 20% or 500 patients per year)

You may not qualify if:

• Mechanical Valve
• Ventricular Assist Device (VAD)
• SDH \>8 mm maximum width or any midline shift at any time point or more than one SDH
• Physician plan to start/restart antiplatelet therapy during trial period
• Acute Injury Score other than head \>=3
• Pregnancy
• Inability to understand need for adherence to study protocol
• Any active pathological bleeding (e.g. no acute blood on most recent CT)
• Hypersensitivity to drug or other label contraindication
• Any bleeding that the investigator deems unsafe to restart DOAC at 1 week post injury, or conversely unsafe to hold DOAC to 4 weeks
• Expected completion of DOAC therapy expected prior to 60 day primary outcome, e.g. 3-6 month VTE therapy
• Concomitant need for strong inducers/inhibitors of p-gp and CYP3A4

Sponsors & Collaborators

• University of Texas at Austin: lead

Study Sites (1)

Dell Seton Medical Center at The University of Texas

Austin, Texas, 78701, United States

Location

MeSH Terms

Conditions

Hemorrhage; Intracranial Hemorrhages; Wounds and Injuries

Interventions

Anticoagulants

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Hematologic Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Truman J Milling, MD

  Seton Dell Medical School Stroke Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Truman J Milling, MD

CONTACT

5124969742; tmilling@ascension.org

Patrick Lawrence

CONTACT

patrick.lawrence@austin.utexas.edu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Neurology

Model Details: The trial will employ an innovative adaptive design using time as a dose (1, 2 and 4 weeks) and adapting randomization probabilities to the better performing doses with a PROBE model to minimize surveillance bias.

Study Record Dates

• First Submitted: January 13, 2020
• First Posted: January 18, 2020
• Study Start: October 1, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): February 1, 2027
• Last Updated: May 19, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: After publication of primary manuscript

Locations

US (1)