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

TRACK-TBI Precision Medicine Phase 2-Option I

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Traumatic Brain Injury

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 50

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • University of California, San Francisco
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania/Penn Presbyterian Medical Center
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

This is a population-based TBI study. All patients presenting with traumatic brain injury and receive a head CT scan as part of standard care within 6 hours of injury are initially eligible.

Description

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)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Moderate to Severe TBI Subjects; 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?

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

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: U.S. Army Medical Research and Development Command
• Investigators: Study Director: Geoffrey T Manley, MD, PhD, University of California, San Francisco; Study Director: Claudia S Robertson, MD, Baylor College of Medicine; Study Director: David O Okonkwo, MD, PhD, University of Pittsburgh Medical Center; Study Director: Ramon Diaz-Arrastia, MD, PhD, University of Pennsylvania; Study Director: Nancy R Temkin, PhD, University of Washington; Study Director: Pratik Mukherjee, MD, PhD, University of California, San Francisco; Study Director: Joseph T Giacino, PhD, Harvard Medical School, Spaulding Rehabilitation Hospital; Study Director: Murray B Stein, MD, MPH, University of California, San Diego; Principal Investigator: Mike McCrea, PhD, ABPP, Medical College of Wisconsin; Principal Investigator: Ramesh Grandhi, MD, MS, University of Utah

Publications and helpful links

General Publications

• Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. J Neurotrauma. 1998 Aug;15(8):573-85. doi: 10.1089/neu.1998.15.573.
• Maas AI, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: past experience and current developments. Neurotherapeutics. 2010 Jan;7(1):115-26. doi: 10.1016/j.nurt.2009.10.022.
• Teasdale G, Jennett B. Assessment and prognosis of coma after head injury. Acta Neurochir (Wien). 1976;34(1-4):45-55. doi: 10.1007/BF01405862.
• Maas AI, Harrison-Felix CL, Menon D, Adelson PD, Balkin T, Bullock R, Engel DC, Gordon W, Orman JL, Lew HL, Robertson C, Temkin N, Valadka A, Verfaellie M, Wainwright M, Wright DW, Schwab K. Common data elements for traumatic brain injury: recommendations from the interagency working group on demographics and clinical assessment. Arch Phys Med Rehabil. 2010 Nov;91(11):1641-9. doi: 10.1016/j.apmr.2010.07.232.
• Manley GT, Diaz-Arrastia R, Brophy M, Engel D, Goodman C, Gwinn K, Veenstra TD, Ling G, Ottens AK, Tortella F, Hayes RL. Common data elements for traumatic brain injury: recommendations from the biospecimens and biomarkers working group. Arch Phys Med Rehabil. 2010 Nov;91(11):1667-72. doi: 10.1016/j.apmr.2010.05.018.
• Duhaime AC, Gean AD, Haacke EM, Hicks R, Wintermark M, Mukherjee P, Brody D, Latour L, Riedy G; Common Data Elements Neuroimaging Working Group Members, Pediatric Working Group Members. Common data elements in radiologic imaging of traumatic brain injury. Arch Phys Med Rehabil. 2010 Nov;91(11):1661-6. doi: 10.1016/j.apmr.2010.07.238.
• Whyte J, Vasterling J, Manley GT. Common data elements for research on traumatic brain injury and psychological health: current status and future development. Arch Phys Med Rehabil. 2010 Nov;91(11):1692-6. doi: 10.1016/j.apmr.2010.06.031.
• Almasy L, Blangero J. Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. Am J Med Genet. 2001 Jan 8;105(1):42-4.
• O'Neil ME, Carlson KF, Storzbach D, Brenner LA, Freeman M, Quinones AR, Motu'apuaka M, Kansagara D. Factors associated with mild traumatic brain injury in veterans and military personnel: a systematic review. J Int Neuropsychol Soc. 2014 Mar;20(3):249-61. doi: 10.1017/S1355617714000204.
• Alsop DC, Detre JA, Golay X, Gunther M, Hendrikse J, Hernandez-Garcia L, Lu H, MacIntosh BJ, Parkes LM, Smits M, van Osch MJ, Wang DJ, Wong EC, Zaharchuk G. Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia. Magn Reson Med. 2015 Jan;73(1):102-16. doi: 10.1002/mrm.25197. Epub 2014 Apr 8.
• Dikmen S, Machamer J, Miller B, Doctor J, Temkin N. Functional status examination: a new instrument for assessing outcome in traumatic brain injury. J Neurotrauma. 2001 Feb;18(2):127-40. doi: 10.1089/08977150150502578.
• McCrea M, Kelly JP, Randolph C. Standardized Assessment of Concussion (SAC): Manual for Administration, Scoring and Interpretation. 2nd ed. Waukesha, WI: CNS Inc; 2000. [Google Scholar]
• Smith GP, Burger GK. Detection of malingering: validation of the Structured Inventory of Malingered Symptomatology (SIMS). J Am Acad Psychiatry Law. 1997;25(2):183-9.
• Reitan, R.M. and D. Wolfson, The Halstead-Reitan neuropsychological test battery: Theory and clinical interpretation. Vol. 4. 1985: Reitan Neuropsychology.
• Finkelstein E, Corso P, Miller T and Associates. The Incidence and Economic Burden of Injuries in the United States. New York (NY): Oxford University Press; 2006.

Helpful Links

• Access to FITBIR data will be according to FITBIR policies.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2021
• Primary Completion (Actual): November 11, 2022
• Study Completion (Estimated): April 9, 2030

Study Registration Dates

• First Submitted: October 20, 2020
• First Submitted That Met QC Criteria: October 20, 2020
• First Posted (Actual): October 26, 2020

Study Record Updates

• Last Update Posted (Actual): April 13, 2025
• Last Update Submitted That Met QC Criteria: April 9, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Concussion; Biomarkers; Neuroimaging; Traumatic Brain Injury; Psychological Health
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries, Traumatic; Brain Injuries
• Other Study ID Numbers: W81XWH-18-2-0042

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The TRACK TBI investigators have created a Data Use Agreement/Human Materials Transfer Agreement (DUA/HTMA) for TRACK-TBI Research Collaborations. This Agreement is for the use of clinical data, neuroimaging, and bio-specimens collected by the TRACK-TBI investigators. All Research Collaborators can submit a written request to the TRACK-TBI Executive Committee.; This study involves research in the area of traumatic brain injury (TBI). The Department of Defense, in collaboration with the National Institutes of Health, has developed the Federal Interagency Traumatic Brain Injury Research (FITBIR) Informatics System, a central repository and resource for sharing data to promote collaboration, accelerate research, and advance knowledge on the characterization, prevention, diagnosis, and treatment of TBI. The TRACK-TBI Investigators will share study data via FITBIR in accordance with FITBIR policy and procedures.
• IPD Sharing Time Frame: Data will become available after study completion.
• IPD Sharing Access Criteria: All Research Collaborations with TRACK-TBI begins with a written request submitted to the TRACK-TBI Executive Committee. The Research Collaboration Proposal form is attached as Appendix 1 in the Research Collaboration Policy available on the TRACK-TBI website.; Access to FITBIR data will be according to FITBIR policies found at https://fitbir.nih.gov/jsp/about/policy.jsp

Drug and device information, study documents

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