Developing and Validating Blood and Imaging BIOmarkers of AXonal Injury Following Traumatic Brain Injury

Completed

• Conditions: Traumatic Brain Injury
• Interventions: Diagnostic Test: MRI; Diagnostic Test: Blood Sampling; Diagnostic Test: Neuropsychological tests; Diagnostic Test: Microdialysis; Diagnostic Test: MRI (advanced)

• Registration Number: NCT03534154
• Lead Sponsor: Imperial College London

Brief Summary

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

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2017-11-30
• Study First Submitted: 2018-04-27
• Study First Submitted QC: 2018-05-11
• Study First Posted: 2018-05-23
• Primary Completion: 2021-04-30
• Study Completion: 2021-12-30
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-29
• Last Update Posted: 2022-03-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 313

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.

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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.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
TBI - microdialysis / adv. MRI / cognitive / clinical	Blood Sampling	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.
TBI - Advanced MRI / bloods / cognitive / clinical outcomes	Neuropsychological tests	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.
TBI - microdialysis / adv. MRI / cognitive / clinical	MRI	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.
Healthy volunteer	Blood Sampling	Single assessment using MRI, bloods and cognitive testing.
TBI - MRI / bloods / cognitive / clinical outcomes	Blood Sampling	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
Healthy volunteer	MRI	Single assessment using MRI, bloods and cognitive testing.
TBI - MRI / bloods / cognitive / clinical outcomes	Neuropsychological tests	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
TBI - Advanced MRI / bloods / cognitive / clinical outcomes	Blood Sampling	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.
TBI - microdialysis / adv. MRI / cognitive / clinical	Neuropsychological tests	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.
TBI - microdialysis / adv. MRI / cognitive / clinical	MRI (advanced)	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.
TBI - MRI / bloods / cognitive / clinical outcomes	MRI	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
TBI - Advanced MRI / bloods / cognitive / clinical outcomes	MRI	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.
TBI - Advanced MRI / bloods / cognitive / clinical outcomes	MRI (advanced)	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.
TBI - microdialysis / adv. MRI / cognitive / clinical	Microdialysis	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.
Healthy volunteer	Neuropsychological tests	Single assessment using MRI, bloods and cognitive testing.

Primary Outcome Measures

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

Trial Locations

Locations (5)

Centre Hospitalier Universitaire Vaudois; 🇨🇭 Lausanne, Switzerland

Fondazione IRCCS, Ca' Granda Ospedale Maggiore Policlinico; 🇮🇹 Milan, Italy

University Medical Centre; 🇸🇮 Ljubljana, Slovenia

IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri"; 🇮🇹 Milan, Italy

Imperial College London; 🇬🇧 London, United Kingdom