Developing and Validating Blood and Imaging BIOmarkers of AXonal Injury Following Traumatic Brain Injury (BIO-AX-TBI)

Observational longitudinal study assessing outcomes following moderate-severe traumatic brain injury (TBI).

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Diagnostic test: MRI; Diagnostic test: Blood Sampling; Diagnostic test: Neuropsychological tests; Diagnostic test: MRI (advanced); Diagnostic test: Microdialysis

Detailed Description

Traumatic brain injury (TBI) occurs when the brain is physically damaged, for example after a car crash. It is common and survivors often have major on-going problems. It is very difficult to predict how patients will do after TBI. One reason for this is that clinicians and researchers are unable to measure all the effects of TBI. An important factor is that the connections between nerve cells are damaged by the impact on the brain of an injury (axonal injury). This damage has been difficult to measure in the past, but new ways to scan the brain and more sensitive ways of picking up the effects of this injury in the blood could change this. In other parts of medicine tests of this type have had a dramatic effect on how clinicians treat patients. For example, the products of heart muscle damage that have leaked into the blood can be used identify a heart attack and guide treatment. Clinicians need similar tests to be available in TBI. This should be possible as the products of axonal injury also leak into the blood and researchers have a sensitive way to pick this up. An accurate test for axonal injury would guide treatment choices and allow clinicians to predict how patients will recover. The investigators have brought together an international team who have been working on different aspects of this problem for many years. Together the investigators will conduct a large study to identify the best measures of axonal injury. The investigators will carefully test whether these measures help predict outcomes and will study where the blood markers come from using a safe method to measure the effects of axonal injury directly from the brain. The work links into some large projects that have already started and will use a standard way to assess patients after their injury. This is important because it will allow researchers to share results across studies. The investigators hope the work will allow us to identify a blood marker for TBI that could be widely used to quickly identify the presence of axonal injury. The investigators will also show what brain imaging measure is best at picking up axonal injury and how best to combine the measures to best predict how patients recover. This will allow doctors to diagnose problems after TBI more accurately, choose the right treatments and give patients and their families accurate advice about what will happen after discharge from hospital.

• Study Type: Observational
• Enrollment (Actual): 313

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy
    • Fondazione IRCCS, Ca' Granda Ospedale Maggiore Policlinico
  • Milan, Italy
    • IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri"
• Slovenia
  • Ljubljana, Slovenia
    • University Medical Centre
• Switzerland
  • Lausanne, Switzerland
    • Centre Hospitalier Universitaire Vaudois
• United Kingdom
  • London, United Kingdom, W12 0NN
    • Imperial College London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

250 traumatic brain injury patients from ITU / major trauma ward.

Description

Inclusion Criteria:

• A diagnosis of moderate/severe traumatic brain injury (TBI) as classified using the Mayo classification system;
• Healthy controls will be age-matched to our TBI patients and will not have a history of significant neurological or psychiatric conditions.

Exclusion Criteria:

• Unwillingness or inability to follow the procedures required
• Bilateral fixed dilated pupils
• For MRI, contra-indication to MRI scanning, assessed by a standard pre-MRI questionnaire (e.g. presence of ferromagnetic implants in the body, claustrophobia, pregnancy) if considered for the imaging strand of the study.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
TBI - MRI / bloods / cognitive / clinical outcomes; Work package 1. In a large multi-centre cohort of adult moderate/severe TBI patients we aim to identify the most informative plasma biomarker(s) of the severity of axonal injury. We will characterise their time course, focusing on neurofilament light (NFL) and tau, and relate these to magnetic resonance imaging (MRI) measures of axonal injury. Using logistic regression we will then test whether these measures contribute to the prediction of clinical outcome at twelve months	Diagnostic test: MRI; Magnetic Resonance Imaging; Diagnostic test: Blood Sampling; Sampling of serum; Diagnostic test: Neuropsychological tests; Battery of tests to assess cognitive function, patient outcomes
TBI - Advanced MRI / bloods / cognitive / clinical outcomes; Work package 2. In a subgroup of the patients recruited to WP1 we will use advanced MRI and longitudinal assessments to provide a more detailed description of the relationship between the plasma biomarkers and outcome after TBI. We will test whether advanced diffusion and myelin integrity measures correlate with plasma biomarkers and whether early plasma biomarker levels predict neurodegeneration measured by progressive atrophy after TBI.	Diagnostic test: MRI; Magnetic Resonance Imaging; Diagnostic test: Blood Sampling; Sampling of serum; Diagnostic test: Neuropsychological tests; Battery of tests to assess cognitive function, patient outcomes; Diagnostic test: MRI (advanced); Advanced MRI
TBI - microdialysis / adv. MRI / cognitive / clinical; Work package 3. In a second subgroup of patients recruited to WP1 we will combine microdialysis, neuroimaging and plasma sampling of axonal proteins to provide a deeper understanding of the mechanisms of axonal injury progression and use this approach to investigate the axonal origin of the plasma biomarkers.	Diagnostic test: MRI; Magnetic Resonance Imaging; Diagnostic test: Blood Sampling; Sampling of serum; Diagnostic test: Neuropsychological tests; Battery of tests to assess cognitive function, patient outcomes; Diagnostic test: MRI (advanced); Advanced MRI; Diagnostic test: Microdialysis; Monitoring of cerebral fluid protein levels
Healthy volunteer; Single assessment using MRI, bloods and cognitive testing.	Diagnostic test: MRI; Magnetic Resonance Imaging; Diagnostic test: Blood Sampling; Sampling of serum; Diagnostic test: Neuropsychological tests; Battery of tests to assess cognitive function, patient outcomes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in diffusion tensor imaging measures over time	Fractional anisotropy (FA)	10 days - 6 weeks, 6 months and 12 months
Brain atrophy rates	Brain tissue volume changes over time.	10 days - 6 weeks, 6 months and 12 months
Change in levels of fluid biomarkers in blood	Neurofilament light and Tau protein	0-5 days, 5-10 days, 10 days - 6 weeks, 6 months and 12 months
Change in levels of fluid biomarkers in cerebral fluid	Neurofilament light and Tau protein	48 hours to 7 days

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: University College, London; Centre Hospitalier Universitaire Vaudois; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico; Istituto Di Ricerche Farmacologiche Mario Negri
• Investigators: Principal Investigator: David Sharp, Imperial College London

Publications and helpful links

General Publications

• Graham NSN, Zimmerman KA, Bertolini G, Magnoni S, Oddo M, Zetterberg H, Moro F, Novelli D, Heslegrave A, Chieregato A, Fainardi E, Fleming JM, Garbero E, Abed-Maillard S, Gradisek P, Bernini A, Sharp DJ. Multicentre longitudinal study of fluid and neuroimaging BIOmarkers of AXonal injury after traumatic brain injury: the BIO-AX-TBI study protocol. BMJ Open. 2020 Nov 10;10(11):e042093. doi: 10.1136/bmjopen-2020-042093.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2017
• Primary Completion (Actual): April 30, 2021
• Study Completion (Actual): December 30, 2021

Study Registration Dates

• First Submitted: April 27, 2018
• First Submitted That Met QC Criteria: May 11, 2018
• First Posted (Actual): May 23, 2018

Study Record Updates

• Last Update Posted (Actual): March 31, 2022
• Last Update Submitted That Met QC Criteria: March 29, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• 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
• Other Study ID Numbers: 230221; MR/R004528/1 (Other Grant/Funding Number: ERA-NET)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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