Restart TICrH Alpha Pilot Protocol, Restarting DOACs After Traumatic Intracranial Hemorrhage

A Pilot Trial of Restarting Direct Oral Anticoagulants After Traumatic Intracranial Hemorrhage

Randomized pilot trial of restarting DOACs at 1 week versus 4 weeks after traumatic intracranial hemorrhage

Study Overview

• Status: Not yet recruiting
• Conditions: Anticoagulants; Increased
• Intervention / Treatment: Drug: Apixaban

Detailed Description

Restart TICrH two-center pilot trial will assign patients with anticoagulant-associated traumatic intracranial hemorrhage to restart anticoagulation at 1 week or 4 weeks. Entry into the trial is primarily driven pragmatically by clinician intent to restart any Direct Oral Anticoagulant (DOAC, i.e. apixaban, rivaroxaban, edoxaban, dabigatran. There is no head to head evidence of superiority of any drug) 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.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Steven Warach, MD PhD; Email: steven.warach@austin.utexas.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Acute traumatic intracranial hemorrhage on anticoagulation for Atrial Fibrillation (AF) or Venous Thromboembolism (VTE)
2. 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 2 points), history of stroke or TIA (2 points), history of heart failure, history of diabetes, history of atherosclerotic vascular disease, female biological sex, history of hypertension)
3. DOAC prescribed at label dose with creatinine clearance adjustments. DOAC at continuation dose, i.e., not initial therapy high doses in the setting of VTE

Exclusion Criteria:

1. Mechanical Valve or Ventricular Assist Device (VAD)
2. SDH >8 mm maximum width or any midline shift at any time point or more than one SDH
3. Physician plan to start/restart antiplatelet therapy during trial period
4. Abbreviated Injury Scale other than head >3
5. Pregnancy
6. Inability to understand need for adherence to study protocol
7. Renal function below DOAC label exclusions
8. Any active pathological bleeding (e.g. no acute blood on 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, e.g. 3-6 month VTE treatment
12. Concomitant need for strong inducers/inhibitors of p-gp and CYP3A4
13. Low body weight (<45kg)
14. Inability to swallow

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 1 week restart; restart DOAC at 1 week post injury at label dose and frequency	Drug: Apixaban; Direct Oral Anticoagulation all at label dose and frequency; Other Names: Dabigatran; Edoxaban; Rivaroxaban
ACTIVE_COMPARATOR: 4 week restart; restart DOAC at 4 weeks post injury at label dose and frequency	Drug: Apixaban; Direct Oral Anticoagulation all at label dose and frequency; Other Names: Dabigatran; Edoxaban; Rivaroxaban

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
60-day composite endpoint	A 60-day composite endpoint that includes the following clinical events: New or expansion of intracranial hemorrhage, other BARC3a or above major hemorrhage 28, stroke, systemic embolism, myocardial infarction, proximal lower extremity deep vein thrombosis, pulmonary embolism and cardiovascular death	60 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disability Rating Scale (0-29 scale range)	Functional Measure	60 days
Modified Rankin Scale (0-6 scale range)	Functional Measure	60 day
Standard Gamble	The standard gamble is the gold standard for analysis of decision making under uncertainty 7. It is an interview technique that begins with a description of a disease state. The patient is then asked to imagine suffering the disease and having a choice between taking a medication that might cure them but also might kill them. The so-called ping-pong method requires the interviewer to start with a hypothetical scenario of 0% probability of cure and 100% probability of a painless instant death. The interviewer then asks the patient if they would take the medication. He then flips the scenario, 100% cure, 0% death. He then goes back and forth between successive scenarios of lower death higher cure and lower cure higher death. Eventually, the patient settles at an equipoise and indecision of whether the risk of dying is worth incurring to take the medication and cure the disease. This is the patient's utility for that disease, expressed as a number between 0 and 1.	pre-randomization (The day before randomization, which must occur within 6 days of index injury) and after endpoints (the day after one of the endpoints occurs. We cannot know precisely when this will occur in the 60 day follow up period)

Collaborators and Investigators

• Sponsor: University of Texas at Austin
• Collaborators: University of Kansas

Publications and helpful links

General Publications

• Milling TJ Jr, Warach S, Johnston SC, Gajewski B, Costantini T, Price M, Wick J, Roward S, Mudaranthakam D, Dula AN, King B, Muddiman A, Lip GYH. Restart TICrH: An Adaptive Randomized Trial of Time Intervals to Restart Direct Oral Anticoagulants after Traumatic Intracranial Hemorrhage. J Neurotrauma. 2021 Jun 1;38(13):1791-1798. doi: 10.1089/neu.2020.7535. Epub 2021 Apr 6.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): July 1, 2021
• Primary Completion (ANTICIPATED): July 1, 2023
• Study Completion (ANTICIPATED): July 1, 2023

Study Registration Dates

• First Submitted: May 10, 2021
• First Submitted That Met QC Criteria: May 14, 2021
• First Posted (ACTUAL): May 19, 2021

Study Record Updates

• Last Update Posted (ACTUAL): May 19, 2021
• Last Update Submitted That Met QC Criteria: May 14, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: anticoagulant; DOAC; restart
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Hemorrhage; Intracranial Hemorrhages; Intracranial Hemorrhage, Traumatic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Dabigatran; Apixaban; Edoxaban
• Other Study ID Numbers: ML42205

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Sharing via BIOLINCC
• IPD Sharing Time Frame: After primary publication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No