Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI)

Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI)

Introduction and Consortium History 

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The TRACK-TBI Consortium is a partnership of top tier academic and Level 1 Trauma Centers across the United States. Launched in 2009, the TRACK-TBI Pilot study (NIH RC2 NS069409) has:

  • Validated the NINDS TBI Common Data Elements (TBI-CDEs).
  • Collected detailed clinical data on 650 subjects across the injury spectrum, along with CT/MRI imaging, blood biospecimens, and detailed outcomes.
  • Built an infrastructure of integrated clinical databases, imaging repositories, biosample repositories, and coordinated multisite/multidisciplinary expertise.
  • Received ongoing financial and in-kind support from patient advocacy foundations and private industry partners in the neuroimaging, pharmaceutical, device, and data management and analytic spaces

From 3 enrolling sites during its pilot phase, TRACK-TBI expanded to 11 sites with the launch of the TRACK-TBI U01 phase in 2013 (NINDS U01 NS086090). 7 new institutions joined the consortium during the U01 phase (2017), resulting in a total of 18 enrolling clinical sites with additional sites providing analytic support.

Goals:

  • Describe the natural history of TBI.
  • Establish precise methods for TBI diagnosis and prognosis.
  • Refine outcome assessments.
  • Compare the effectiveness and costs of TBI care.

The extensive protocols empower rich, multidimensional characterization of the clinical, neuroimaging, and blood-based biomarker features of TBI. TRACK-TBI has amassed the world’s largest and most comprehensive serial collection of standardized TBI neuroimaging (CT and MRI), using structural, functional, and diffusion phantoms for quantitative imaging, and developed automated pipelines for imaging quality assurance. The TRACK-TBI study followed participants longitudinally for one year from time of injury.

With the close of U01 funding in 2018, continued enrollment into the TRACK-TBI protocol was supported by an unrestricted gift from the National Football League (i.e., “Post-U01 cohort” – for more information about this cohort, see the below section “TRACK-TBI U01 vs. “Post-U01”).

As of July 2020, TRACK-TBI U01+Post-U01 has enrolled >3050 TBI subjects and >350 orthopedic control subjects. 

TRACK-TBI Longitudinal (TRACK-TBI LONG)

TRACK-TBI LONG, launched in May 2019, extends follow-up of the deeply phenotyped TRACK-TBI cohort into the chronic phase. This is the first and largest study of incident TBI to couple comprehensive multi-year clinical trajectories with advanced neuroimaging and proteomic biomarkers.

Goals:

  • Connect with participants enrolled in the TRACK-TBI-II study to assess their functional status two or more years after their original study injury.
  • Elucidate TBI’s natural history.
  • Identify individuals most at risk for unfavorable outcomes.
  • Initiate development of diagnostic, prognostic, and therapeutic/ management tools for this heterogeneous condition. 

TRACK-TBI LONG expands upon the original TRACK-TBI study protocol. TBI and Control participants from the TRACK-TBI U01 study (n~3000), as well as additional participants enrolled under the Post-U01 phase of the study (n~400+ as of July 2020), will be eligible for up to 3 annual TRACK-TBI LONG Telephone Assessments.

Sites with the TRACK-TBI protocol have completed over 1,800 LONG follow ups. Of these, 594 participants have completed a follow up at a second time point, and 30 at a third time point. 

TRACK-TBI is supported by funding through a competitive grant from the National Football League Scientific Advisory Board.

Clinical Validation of Serum Neurofilament Light as a Biomarker of Traumatic Axonal Injury (TRACK-TBI BIO)

Traumatic brain injury (TBI) is one of the leading causes of mortality and morbidity affecting humanity, and a recognized risk factor for late-life neurodegenerative disorders. The absence of validated biomarkers in the neurotrauma field is a barrier to drug development in this area. Consequently, there are no disease-modifying therapies that successfully limit the burden of TBI.

Traumatic axonal injury (TAI) is a common pathologic consequence of TBI and underlies the most disabling consequences of TB injury. Recent breakthroughs in pre-clinical models indicate that novel therapeutic interventions are effective in promoting resilience of injured axons and improving neurologic outcome after experimental TBI. Successful translation of such therapies will require prognostic biomarkers that can measure TAI in individual patients, as well as pharmacodynamic biomarkers to measure the efficacy of such treatments. Currently, the best biomarker for TAI is fractional anisotropy (FA) and mean diffusivity (MD) of white matter tracts, measured using diffusion tensor imaging (DTI) MRI. This technique, while robust, is poorly suited for dynamic longitudinal assessments, and measures the end-result of axonal degeneration, rather than earlier stages in the neurodegenerative process. The recent ability to assay axonal proteins in peripheral blood has made it potentially feasible to assess TAI rapidly, inexpensively, and longitudinally. The goal of this project is to clinically validate the axonal protein neurofilament light chain (NfL) as a prognostic biomarker of TAI. 

The TRACK-TBI Biomarker Project NF-L (TRACK-TBI BIO NF-L) will extend the follow-up periods for TRACK-TBI participants from 1 to 5 years. The extensive clinical, imaging, and biomarker data that has already been collected in these subjects will allow for the identification of risk factors, co-morbidities, and prognostic biomarkers of TBI. Consequently, the extension of study follow-up will help to determine negative neurological and psychological outcomes of individuals who experienced a TBI compared to healthy controls. A secondary objective of this study is to validate serum NF-L as a biomarker of traumatic axonal injury, and through this project obtain data that will allow us, at the end of the 5-year project period, to submit a Qualification Plan to the Center for Drug Evaluation and Research at FDA for qualification of serum- NF-L as a Drug Development Tool.

The TRACK-TBI Biomarker Project Tau/pTau (TRACK-TBI BIO Tau/PTau aims to Validation of Tau and P-Tau as acute and subacute prognostic biomarkers for complicated mild TBI.

TRACK-TBI Epileptogenesis Project (TRACK-TBI EPI) 

Post-traumatic epilepsy (PTE) is a common complication of traumatic brain injury (TBI), occurring in up to 20% of civilian patients and as many as 50% of military service members who suffer severe brain trauma, and 3-5% of those who suffer moderate TBI.[10] Epilepsy resulting from brain trauma is often difficult to control with medical therapy, and is the cause of epilepsy in approximately 5% of patients referred to specialized epilepsy centers. PTE can be the result of TBI of any severity, although the risk is higher from severe TBI. PTE can arise through a variety of mechanisms, which may co-exist within a single patient.[11] Focal brain injury, which results from penetrating trauma or focal contusions can result in epileptogenesis. Closed head injury can also produce diffuse injury, with shearing of axons and blood vessels, diffuse edema and ischemia, and secondary cellular damage through the release of inflammatory mediators. The clinical features of epilepsy, such as the frequency and severity of seizures, prevalence of associated co-morbidities, and responsiveness to therapy, may differ among these diverse mechanisms. Additionally, the neurophysiologic, and imaging features of epileptogenicity also likely differ, and it is likely that a sophisticated understanding of the subtypes of epilepsy resulting from brain trauma will be required to successfully develop anti-epileptogenic therapies. 

Funded in March 2019, the overarching goal of the TRACK-TBI Epileptogenesis Project (TRACK-TBI EPI) is to determine how post-traumatic epilepsy (PTE) contributes to the negative neurological and psychological outcomes of individuals who experienced a traumatic brain injury (TBI), compared to subjects with comparable TBI without PTE. TRACK-TBI EPI aims to extend the follow-up period of the TRACK-TBI cohort up to 5 years after injury, which will allow identification of >90% of those who may have developed PTE. Using the TRACK-TBI NINDS PTE Screening Questionnaire, we will identify participants who screen positive for PTE and consent them to undergo a detailed clinical evaluation with an epileptologist. With data collected via a combination of follow up phone screening and in-person visits, the primary study endpoint will assess the relationship between TBI severity and epileptogenesis. This data will provide the first comprehensive longitudinal phenotyping of subjects with PTE from the moment of TBI through their epilepsy diagnosis and treatment.