Clinical Randomisation of an Anti-fibrinolytic in Symptomatic Mild Head Injury in Older Adults (CRASH-4)

Intramuscular Tranexamic Acid for the Treatment of Symptomatic Mild Traumatic Brain Injury in Older Adults: a Randomised, Double-blind, Placebo-controlled Trial

Tranexamic acid (TXA) reduces head injury deaths. The CRASH-4 trial aims to assess the effects of early intramuscular TXA on intracranial haemorrhage, disability, death, and dementia in older adults with symptomatic mild head injury

Study Overview

• Status: Recruiting
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Tranexamic Acid 500 MG

Detailed Description

TXA reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. Results from randomised trials (CRASH-3 and NCT01990768) show that early treatment with TXA (given intravenously) reduces head injury deaths (pooled RR 0.89, 95% CI 0.80-0.99). In the CRASH-3 trial, the reduction in head injury deaths with TXA was largest in patients with mild and moderate head injuries, particularly if patients were treated soon after injury. However, the CRASH-3 trial included mild TBI patients only if they had intracranial bleeding on CT scan. It is uncertain whether the results apply to mild TBI patients more generally. CRASH-4 is a randomised, double blind, placebo-controlled trial in symptomatic mild TBI in about 10,000 older adults. The pilot phase will include about 500 patients. The trial aims to provide reliable evidence about the effects of early intramuscular TXA on intracranial haemorrhage, disability, death, and dementia in older adults with symptomatic mild head injury.

• Study Type: Interventional
• Enrollment (Anticipated): 10000
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Haleema Shakur-Still; Phone Number: +4407714139500; Email: Haleema.Shakur@lshtm.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, E1 1FR
    • Recruiting
    • The Royal London Hospital
  • London, United Kingdom, SW17 0QT
    • Recruiting
    • St George's Hospital
    • Contact: Heather Jarman

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 50 years or older (actual or estimated)
• History or evidence of head injury (e.g. laceration, bruise, swelling or pain in head or face)
• GCS ≥ 13

• Has one or more of the following:

  1. has or had any impaired consciousness (loss of consciousness, amnesia, or confusion)
  2. nausea or vomiting
• Within 3 hours of injury (do not include if interval cannot be estimated e.g. patient unable to confirm time of fall or patient found on floor after an unwitnessed fall and home alone)
• Not living in a nursing home, mental health institution or prison
• Patient will be conveyed to or is admitted to a participating hospital

Exclusion Criteria:

- TXA not clearly indicated (e.g. major bleeding) or contraindicated (e.g. suspected stroke)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active; A single dose of Tranexamic acid 500mg given by intramuscular injection	Drug: Tranexamic Acid 500 MG; given once as an intramuscular injection
Placebo Comparator: Placebo; One Injection of the placebo which is 10 mL Sodium Chloride (0.9%)	Drug: Tranexamic Acid 500 MG; given once as an intramuscular injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Emergency department discharge	discharge	within 24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial bleeding on CT scan	any bleeding on the last scan conducted within 48 hours of randomisation	within 48 hours
Head injury related death	In-hospital head injury-related death within 48 hours of injury	within 48 hours
All cause mortality	Cause of death will be described	within 28 days
Disability	The Barthel scale will be used to assess functional disability	within 28 days
Global assessment of ability to self-care	Scale of 1 to 5	within 28 days
Neurosurgery	receipt of neurosurgery and type	within 28 days
Days in ICU	Number of days	within 28 days
Re-admission to hospital	readmission after discharge	within 28 days
Vascular occlusive events	pulmonary embolism, myocardial infarction, deep vein thrombosis and stroke	within 28 days
Seizures		within 28 days
Intramuscular injection site reaction	frequency and type of reactions	within 28 days
Pneumonia		within 28 days
Adverse events	Any untoward medical occurrence (other than pre-specified outcomes)	within 28 days
Dementia	The occurrence of all-cause dementia will be determined 12 months after randomisation. Dementia will be identified through linkage to routinely collected health-care data.	1 year

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Investigators: Study Chair: Haleema Shakur-Still, London School of Hygiene and Tropical Medicine; Study Chair: Ian Roberts, London School of Hygiene and Tropical Medicine

Publications and helpful links

Helpful Links

• Trial website
• TXA background information

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2021
• Primary Completion (Anticipated): March 31, 2024
• Study Completion (Anticipated): March 31, 2025

Study Registration Dates

• First Submitted: August 18, 2020
• First Submitted That Met QC Criteria: August 18, 2020
• First Posted (Actual): August 21, 2020

Study Record Updates

• Last Update Posted (Actual): January 5, 2023
• Last Update Submitted That Met QC Criteria: January 4, 2023
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Traumatic brain injury, tranexamic acid, older adults
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antifibrinolytic Agents; Hemostatics; Coagulants; Tranexamic Acid
• Other Study ID Numbers: 2020-KEP-456; 2020-003391-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Data will be shared publicly when all planned analyses are completed by the CRASH-4 Trial Collaborators. This will be hosted on freebird.lshtm.ac.uk
• IPD Sharing Access Criteria: Totally anonymised data (without random allocation, patient, country and site identifiers) will be freely available.Where random allocation codes, country/site identifiers are requested, appropriate pre-specified analysis plan will need to be submitted to the Trial Management Group for review and if necessary, appropriate Ethics Committee approval will be required.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

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