Transforming Research and Clinical Knowledge in Traumatic Brain Injury

Effective treatment of traumatic brain injury (TBI) remains one of the greatest unmet needs
in public health. After 3 decades of failed clinical trials, a new approach is needed. Our
proposal, Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI),
establishes a public-private partnership of experienced TBI investigators, and philanthropic
and industry collaborators, who share a mission to accelerate TBI research. TRACK-TBI will
create a large, high quality database that integrates clinical, imaging, proteomic, genomic,
and outcome biomarkers to establish more precise methods for TBI diagnosis and prognosis,
refine outcome assessment, and compare the effectiveness and costs of TBI care.

We hypothesize that this approach will permit investigators to better characterize and
stratify patients, allow meaningful comparisons of treatments and outcomes, and improve the
next generation of clinical trials. We have built on the TRACK-TBI Pilot study (NCT01565551)
and our team's precompetitive collaboration, forged by participation in the TBI Common Data
Elements project (TBI-CDE) and the International TBI Research Initiative (InTBIR). Having
provided the index dataset for the Federal Interagency TBI Research database (FITBIR), we now
propose the following Specific Aims:

Specific Aim 1. To create a widely accessible, comprehensive TBI Information Commons that
integrates clinical, imaging, proteomic, genomic, and outcome biomarkers from subjects across
the age and injury spectra, and provides analytic tools and resources to support TBI
research. Multi- disciplinary teams across 11 sites will enroll 3000 subjects of all ages
across the injury spectrum of concussion to coma. Utilizing TBI-CDEs, along with uniform
standards for acquiring multi-site MRI data, we will expand the TRACK-TBI Pilot informatics
platform, leveraging existing informatics tools to populate FITBIR, yielding a resource for
current and future TBI research and international collaboration.

Specific Aim 2. To validate imaging, proteomic, and genetic biomarkers that will improve
classification of TBI, permit appropriate selection and stratification of patients for
clinical trials, and contribute to the development of a new taxonomy for TBI. We hypothesize
that validated imaging, proteomic, and genetic biomarkers will permit improved patient
classification, beyond traditional categories of mild, moderate and severe TBI.

Subaim 2.1. To establish prognostic imaging biomarkers for TBI based on patho-anatomic
analysis of CT and MRI, as well as quantitative MR volumetrics, diffusion tensor imaging
(DTI), and resting state functional MRI (R-fMRI).

Subaim 2.2. To identify blood-based biomarkers that will provide additional diagnostic and
prognostic information with which to identify TBI phenotypes that can be targeted by specific
therapies.

Subaim 2.3. To identify common polymorphisms in candidate genes associated with outcome after
TBI, and to elucidate causal molecular mechanisms of injury, response, and repair.

Subaim 2.4. To construct a multidimensional TBI classification system incorporating data from
multiple domains that will define homogeneous classes of patients suitable for clinical trial
inclusion.

Specific Aim 3. To evaluate a flexible outcome assessment battery comprised of a broad range
of TBI common data elements that enables assessment of multiple outcome domains across all
phases of recovery and at all levels of TBI severity. When compared with the current gold
standard, the Glasgow Outcome Scale Extended (GOSE), we hypothesize that a flexible and more
discriminating outcome battery reflecting multiple functional domains will more precisely and
efficiently capture outcomes across the course of recovery, at all levels of TBI severity.

Subaim 3.1. To improve the granularity and breadth of TBI outcomes using a flexible outcome
assessment battery that enables basic neurocognitive assessment in subjects too impaired to
undergo standard neuropsychological testing, and comprehensive assessment of cognition,
functional status, mental health, social participation, and quality of life in those
cognitively intact enough to provide valid results.

Subaim 3.2. To determine the efficiency of a flexible outcome assessment battery, as compared
with the GOSE, in reducing sample sizes needed to detect differences between groups.

Subaim 3.3. To identify specific TBI phenotypes amenable to targeted interventions, by
relating patient classification factors (Subaim 2.4) to different outcome factor scores
(Subaim 3.1).

Specific Aim 4. To determine which tests, treatments, and services are effective and
appropriate for which TBI patients, and use this evidence to recommend practices that offer
the best value. We will use established comparative effectiveness research (CER) and health
economics methods to evaluate the ability of each clinical practice to improve outcomes while
containing costs.

Subaim 4.1. To identify patients currently admitted to an ICU who could be safely and
effectively cared for in a floor bed or discharged home with outpatient management, and to
estimate the health and economic impact of changing the management of these patients.

Subaim 4.2. To determine whether routine follow up improves TBI outcomes and minimizes their
economic burden.

Subaim 4.3. To assess variability in management of patients taking antiplatelet agents at the
time of TBI, and the effect of management on progression of intracranial hemorrhage, need for
craniotomy, and outcome.

We expect that achievement of these Specific Aims will advance our understanding of TBI,
improve clinical trial design, lead to more effective patient-specific treatments, and
improve outcome after TBI.

Inclusion Criteria:

- Age 18-100 (some sites also enrolling pediatric patients)

- Documented/verified TBI by ACRM Criteria

- Injury occurred within 24 hours of ED arrival

- Acute brain CT as part of clinical care

- Visual acuity and hearing adequate for outcomes testing

- Fluency in English (some sites also enrolling Spanish speakers)

Exclusion Criteria:

- Significant polytrauma that would interfere with follow-up and outcome assessment

- Prisoners or patients in custody

- Pregnancy in female subjects

- Patients on psychiatric hold (e.g. 5150, 5250)

- Major debilitating baseline mental health disorders (e.g. schizophrenia or bipolar
disorder) that would interfere with the validity of outcome assessment due to TBI

- Major debilitating neurological disease (e.g. stroke, CVA, dementia, tumor) impairing
baseline awareness, cognition, or validity of outcome assessment due to TBI

- Significant history of pre-existing conditions that would interfere with likelihood of
follow-up and validity of outcome assessment due to TBI (e.g. major substance abuse,
alcoholism, end-stage cancers, learning disabilities, developmental disorders)

- Contraindications for MR (for CA+MRI cohort)

- Low likelihood of follow-up (e.g. participant or family indicating low interest,
residence in another state or country, homelessness or lack of reliable contacts)

- Current participant in an interventional trial (e.g. drug, device, behavioral)

- Non-English speakers as most outcome measures are normed in the English language.