Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Precision Medicine Phase 2 Option 1

Study Overview
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Brief Summary
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This study is being conducted to validate early and ultra-early blood-based and novel imaging biomarkers of Diffuse Axonal Injury (DAI), Microvascular Injury (MVI), and neuroinflammation that may serve as predictive and pharmacodynamic biomarkers in a new cohort of moderate-severe TRACK-TBI subjects. The study team will enroll a cohort of moderate to severe TBI subjects (N=50), stratified according to VA/DoD criteria for these injury severities through the existing TRACK-TBI network sites to obtain novel advanced neuroimaging and more frequent biomarker sampling. Subjects will be assessed over 3 months.

Detailed Description
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In 2009, the multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury Consortium was implemented to characterize the clinical, magnetic resonance imaging (MRI), and blood-based biomarker features of TBI to inform design of next-generation precision medicine clinical trials in TBI. Over the past 10+ years, TRACK-TBI has been supported by National Institute of Neurological Disorders and Stroke (NINDS), Department of Defense (DoD), Department of Energy (DoE), the National Football League, and other philanthropic and industry partners. TRACK-TBI has enrolled >3000 control and TBI subjects across the injury spectrum at 18 US Level 1 Trauma Centers. This effort has established the world's largest collection of TBI imaging studies and bio-specimens. The study results are already being adopted into clinical research and bedside practice. The TRACK-TBI Consortium is now primed to deliver on critical military and public health knowledge gaps and needs: objective classification of TBI based on what is termed as mechanistic endophenotypes, e.g., diffuse axonal injury (DAI), microvascular injury (MVI), and neuroinflammation. An endophenotype is an internal phenotype discoverable by biochemical, physiological, radiological, pathological, or other techniques, which is intermediate between a complex phenotype and the presumptive genetic or environmental contribution to a disease. Endophenotypes are quantitative, continuous variables, unlike a phenotype which is usually a binary, categorical variable. These mechanistic endophenotypes, defined by imaging and blood-based biomarkers, will direct targeted treatments based on mechanism, providing the tools needed for successful execution of precision medicine clinical trials. To achieve the goal of precision medicine in TBI, it is necessary to identify subgroups of TBI patients that will respond to a targeted therapy. Investigators will assess putative blood-based and neuroimaging biomarkers for DAI, MVI, and neuroinflammation. Fluid biomarkers complement imaging markers and may provide important tools for precision medicine clinical trials. Investigators will collect acute data (early and ultra-early i.e., hours-days following injury), to validate the utility of these biomarkers in defining TBI mechanistic endophenotypes for use in clinical trials. Specific Aim for TRACK-TBI Precision Medicine Phase 2-Option 1: To validate early and ultra-early blood based and novel imaging biomarkers of DAI, MVI, and neuroinflammation that may serve as predictive and pharmacodynamic biomarkers in a cohort of moderate-severe subjects.

Official Title
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TRACK-TBI Precision Medicine Phase 2-Option I

Conditions
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Traumatic Brain Injury

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 65y inclusive History or evidence of TBI, according to DoD-VA criteria Glasgow Coma Scale (GCS) 3 - 15 after resuscitation in the ED Head CT with evidence of trauma-related abnormality (except for isolated epidural hematoma (EDH)) Ability to undergo MRI within 48 hours of injury Ability to obtain informed consent from participant or Legally Authorized Representative (LAR) within 6 hours of injury Fluency in English or Spanish Exclusion Criteria: Unstable respiratory or hemodynamic status Evidence of penetrating brain injury Isolated EDH as only trauma-related CT abnormality Systemic traumatic injury that would preclude participation in study, which is expected to result in long-term disability not related to TBI Evidence of serious infectious complications (sepsis, bacteremia, multilobar pneumonia) Acute ischemic heart disease (myocardial infarction or unstable angina) History of syncope or hypotension Systolic blood pressure (SBP) < 90 mm Hg, Diastolic blood pressure (DBP)< 40 mm Hg for longer than 5 minutes History or evidence of active malignancy History of pre-existing neurologic disorder, such as dementia, mild cognitive impairment, uncontrolled epilepsy, multiple sclerosis, strokes, brain tumors, prior severe TBI, or other disorder that may confound interpretation of MRI or neuropsychological results History of pre-existing disabling mental illness, such as major depression or schizophrenia History or evidence of chronic heart failure or chronic renal failure Low likelihood of follow-up (e.g., participant or family indicating low interest, residence in another state or country, unhoused or lack of reliable contacts) Women who are pregnant or breast-feeding Prisoners or patients in custody Patients on psychiatric hold (e.g. 5150, 5250)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Moderate to Severe TBI Subjects<br>Adult patients (age 18-65y inclusive) presenting to the Emergency Department (ED) with a history of acute TBI as per American Congress of Rehabilitation Medicine (ACRM) Criteria (i.e., patient has sustained a traumatically-induced physiological disruption of brain function). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Specimen for Analysis of Biomarkers | Using advanced blood-based assay platforms, levels of blood biomarkers neurofilament light chain (NfL), Tau, Interleukin 6 (IL6), Interleukin (IL10), and Tumor Necrosis Factor (TNF) will be measured to validate their utility as early predictive and pharmacodynamic biomarkers for Diffuse Axonal Injury (DAI), Microvascular Injury (MVI), and Neuroinflammation. In addition, Ubiquitin C-terminal Hydrolase L1 (UCH-L1)/Glial fibrillary acidic protein (GFAP) markers will also be assayed for comparison. All biomarkers will be measured in picograms/milliliter (pg/mL). | < 6 hours from the time of TBI | 
| Blood Specimen for Analysis of Biomarkers | Using advanced blood-based assay platforms, levels of blood biomarkers neurofilament light chain (NfL), Tau, Interleukin 6 (IL6), Interleukin (IL10), and Tumor Necrosis Factor (TNF) will be measured to validate their utility as early predictive and pharmacodynamic biomarkers for Diffuse Axonal Injury (DAI), Microvascular Injury (MVI), and Neuroinflammation. In addition, Ubiquitin C-terminal Hydrolase L1 (UCH-L1)/Glial fibrillary acidic protein (GFAP) markers will also be assayed for comparison. All biomarkers will be measured in picograms/milliliter (pg/mL). | 12 hours from the time of TBI | 
| Blood Specimen for Analysis of Biomarkers | Using advanced blood-based assay platforms, levels of blood biomarkers neurofilament light chain (NfL), Tau, Interleukin 6 (IL6), Interleukin (IL10), and Tumor Necrosis Factor (TNF) will be measured to validate their utility as early predictive and pharmacodynamic biomarkers for Diffuse Axonal Injury (DAI), Microvascular Injury (MVI), and Neuroinflammation. In addition, Ubiquitin C-terminal Hydrolase L1 (UCH-L1)/Glial fibrillary acidic protein (GFAP) markers will also be assayed for comparison. All biomarkers will be measured in picograms/milliliter (pg/mL). | 24 hours from the time of TBI | 
| Blood Specimen for Analysis of Biomarkers | Using advanced blood-based assay platforms, levels of blood biomarkers neurofilament light chain (NfL), Tau, Interleukin 6 (IL6), Interleukin (IL10), and Tumor Necrosis Factor (TNF) will be measured to validate their utility as early predictive and pharmacodynamic biomarkers for Diffuse Axonal Injury (DAI), Microvascular Injury (MVI), and Neuroinflammation. In addition, Ubiquitin C-terminal Hydrolase L1 (UCH-L1)/Glial fibrillary acidic protein (GFAP) markers will also be assayed for comparison. All biomarkers will be measured in picograms/milliliter (pg/mL). | Day 2 from the time of TBI | 
| Blood Specimen for Analysis of Biomarkers | Using advanced blood-based assay platforms, levels of blood biomarkers neurofilament light chain (NfL), Tau, Interleukin 6 (IL6), Interleukin (IL10), and Tumor Necrosis Factor (TNF) will be measured to validate their utility as early predictive and pharmacodynamic biomarkers for Diffuse Axonal Injury (DAI), Microvascular Injury (MVI), and Neuroinflammation. In addition, Ubiquitin C-terminal Hydrolase L1 (UCH-L1)/Glial fibrillary acidic protein (GFAP) markers will also be assayed for comparison. All biomarkers will be measured in picograms/milliliter (pg/mL). | Day 3 from the time of TBI | 
| Blood Specimen for Analysis of Biomarkers | Using advanced blood-based assay platforms, levels of blood biomarkers neurofilament light chain (NfL), Tau, Interleukin 6 (IL6), Interleukin (IL10), and Tumor Necrosis Factor (TNF) will be measured to validate their utility as early predictive and pharmacodynamic biomarkers for Diffuse Axonal Injury (DAI), Microvascular Injury (MVI), and Neuroinflammation. In addition, Ubiquitin C-terminal Hydrolase L1 (UCH-L1)/Glial fibrillary acidic protein (GFAP) markers will also be assayed for comparison. All biomarkers will be measured in picograms/milliliter (pg/mL). | Day 5 from the time of TBI | 
| Blood Specimen for Analysis of Biomarkers | Using advanced blood-based assay platforms, levels of blood biomarkers neurofilament light chain (NfL), Tau, Interleukin 6 (IL6), Interleukin (IL10), and Tumor Necrosis Factor (TNF) will be measured to validate their utility as early predictive and pharmacodynamic biomarkers for Diffuse Axonal Injury (DAI), Microvascular Injury (MVI), and Neuroinflammation. In addition, Ubiquitin C-terminal Hydrolase L1 (UCH-L1)/Glial fibrillary acidic protein (GFAP) markers will also be assayed for comparison. All biomarkers will be measured in picograms/milliliter (pg/mL). | Week 4 from the time of TBI | 
| Blood Specimen for Analysis of Biomarkers | Using advanced blood-based assay platforms, levels of blood biomarkers neurofilament light chain (NfL), Tau, Interleukin 6 (IL6), Interleukin (IL10), and Tumor Necrosis Factor (TNF) will be measured to validate their utility as early predictive and pharmacodynamic biomarkers for Diffuse Axonal Injury (DAI), Microvascular Injury (MVI), and Neuroinflammation. In addition, Ubiquitin C-terminal Hydrolase L1 (UCH-L1)/Glial fibrillary acidic protein (GFAP) markers will also be assayed for comparison. All biomarkers will be measured in picograms/milliliter (pg/mL). | Week 6 from the time of TBI | 
| Blood Specimen for Analysis of Biomarkers | Using advanced blood-based assay platforms, levels of blood biomarkers neurofilament light chain (NfL), Tau, Interleukin 6 (IL6), Interleukin (IL10), and Tumor Necrosis Factor (TNF) will be measured to validate their utility as early predictive and pharmacodynamic biomarkers for Diffuse Axonal Injury (DAI), Microvascular Injury (MVI), and Neuroinflammation. In addition, Ubiquitin C-terminal Hydrolase L1 (UCH-L1)/Glial fibrillary acidic protein (GFAP) markers will also be assayed for comparison. All biomarkers will be measured in picograms/milliliter (pg/mL). | 3 Months from the time of TBI | 
| 3 Tesla Brain Structural and Functional Magnetic Resonance Imaging (MRI) | This study aims to validate early and ultra-early novel imaging biomarkers in the acute phase after injury. In addition to volumetrics, Diffuse Tensor Imaging (DTI) and Resting State Functional Magnetic Resonance Imaging (rs-fMRI), the MRI protocol will incorporate novel imaging measures of axonal density using neurite density index (NDI) from Neurite Orientation Dispersion And Density Imaging (NODDI) analysis of multi-shell diffusion MRI, cerebral blood flow using Arterial Spin Labeled (ASL) perfusion, and neuroinflammation using free water content isotropic diffusion fraction (FISO) from NODDI analysis of multi-shell diffusion MRI. | Within 24-48 hours from the time of TBI | 
| 3 Tesla Brain Structural and Functional Magnetic Resonance Imaging (MRI) | This study aims to validate early and ultra-early novel imaging biomarkers in the acute phase after injury. In addition to volumetrics, Diffuse Tensor Imaging (DTI) and Resting State Functional Magnetic Resonance Imaging (rs-fMRI), the MRI protocol will incorporate novel imaging measures of axonal density using neurite density index (NDI) from Neurite Orientation Dispersion And Density Imaging (NODDI) analysis of multi-shell diffusion MRI, cerebral blood flow using Arterial Spin Labeled (ASL) perfusion, and neuroinflammation using free water content isotropic diffusion fraction (FISO) from NODDI analysis of multi-shell diffusion MRI. | 2 Weeks from the time of TBI | 
| 3 Tesla Brain Structural and Functional Magnetic Resonance Imaging (MRI) | This study aims to validate early and ultra-early novel imaging biomarkers in the acute phase after injury. In addition to volumetrics, Diffuse Tensor Imaging (DTI) and Resting State Functional Magnetic Resonance Imaging (rs-fMRI), the MRI protocol will incorporate novel imaging measures of axonal density using neurite density index (NDI) from Neurite Orientation Dispersion And Density Imaging (NODDI) analysis of multi-shell diffusion MRI, cerebral blood flow using Arterial Spin Labeled (ASL) perfusion, and neuroinflammation using free water content isotropic diffusion fraction (FISO) from NODDI analysis of multi-shell diffusion MRI. | 3 Months from the time of TBI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glasgow Outcome Scale Extended (GOSE) | The GOSE provides an overall measure of functional status based on information on cognition, independence, employability, and social/community participation collected via structured interview. Individuals are described by one of the eight outcome categories: Dead (1); Vegetative State (2); Lower Severe Disability (3); Upper Severe Disability (4); Lower Moderate Disability (5); Upper Moderate Disability (6); Lower Good Recovery (7) and Upper Good Recovery (8). Good Recovery is defined as a score of 7-8, Moderate Disability is defined by a score of 5-6 and Severe Disability is defined by a score of 3-4. | 2 Weeks from the time of TBI | 
| Glasgow Outcome Scale Extended (GOSE) | The GOSE provides an overall measure of functional status based on information on cognition, independence, employability, and social/community participation collected via structured interview. Individuals are described by one of the eight outcome categories: Dead (1); Vegetative State (2); Lower Severe Disability (3); Upper Severe Disability (4); Lower Moderate Disability (5); Upper Moderate Disability (6); Lower Good Recovery (7) and Upper Good Recovery (8). Good Recovery is defined as a score of 7-8, Moderate Disability is defined by a score of 5-6 and Severe Disability is defined by a score of 3-4. | 6 Weeks from the time of TBI | 
| Glasgow Outcome Scale Extended (GOSE) | The GOSE provides an overall measure of functional status based on information on cognition, independence, employability, and social/community participation collected via structured interview. Individuals are described by one of the eight outcome categories: Dead (1); Vegetative State (2); Lower Severe Disability (3); Upper Severe Disability (4); Lower Moderate Disability (5); Upper Moderate Disability (6); Lower Good Recovery (7) and Upper Good Recovery (8). Good Recovery is defined as a score of 7-8, Moderate Disability is defined by a score of 5-6 and Severe Disability is defined by a score of 3-4. | 3 Months from the time of TBI | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Traumatic Brain Injury, Biomarkers, Neuroimaging, Psychological Health, Concussion