Transforming Research and Clinical Knowledge in Traumatic Brain Injury

Study Overview
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Brief Summary
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The overall goal of Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study is to determine the relationships among the clinical, neuroimaging, cognitive, genetic and proteomic biomarker characteristics for the entire spectrum of TBI from concussion to coma. TRACK-TBI will validate biomarkers and outcome measures for clinical trials, advance diagnostic and prognostic models for TBI and improve clinical trial design. The Investigators are enrolling patients within 24 hours of injury who present to a TRACK-TBI site with a brain injury that meets ACRM criteria and receives a clinically indicated head CT.

Detailed Description
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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. The Investigators 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. The Investigators 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), the Investigators 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, the Investigators 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. The Investigators 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), the Investigators 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. The Investigators 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. The Investigators 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.

Official Title
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Transforming Research and Clinical Knowledge in Traumatic Brain Injury

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Behavioral: In-Person Outcome Assessment
* Behavioral: Phone Outcome Assessment
* Procedure: 3T Magnetic Resonance Imaging (MRI)
* Procedure: Blood Draw for Plasma, DNA, Serum, RNA


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 100 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 |
| --- | --- |
| Comprehensive Assessment with MRI<br>In-Person Outcome Assessment at 2 weeks, 6 months, and 12 months. Phone Outcome Assessment at 3 months. 3T Magnetic Resonance Imaging (MRI) at 2 weeks and 6 months. Blood Draw for Plasma, DNA, Serum, RNA at baseline, in hospital (if applicable), 2 weeks, and 6 months (DNA at baseline only). | Behavioral: In-Person Outcome Assessment<br>* NIH Flexible Outcome Assessment Battery Framework Measures In-Person at 2 Weeks, 6 Months, and 12 Months, and by Phone at 3 Months.<br>Procedure: 3T Magnetic Resonance Imaging (MRI)<br>* 3T Research MRI at 2 weeks and 6 months.<br>Procedure: Blood Draw for Plasma, DNA, Serum, RNA<br>* Blood Draw for Plasma, DNA, Serum, RNA at baseline, in hospital (if applicable), 2 weeks, and 6 months (DNA at baseline only).<br>|
| Comprehensive Assessment without MRI<br>In-Person Outcome Assessment at 2 weeks, 6 months, and 12 months. Phone Outcome Assessment at 3 months. Blood Draw for Plasma, DNA, Serum, RNA at baseline, in hospital (if applicable), 2 weeks, and 6 months (DNA at baseline only). | Behavioral: In-Person Outcome Assessment<br>* NIH Flexible Outcome Assessment Battery Framework Measures In-Person at 2 Weeks, 6 Months, and 12 Months, and by Phone at 3 Months.<br>Procedure: 3T Magnetic Resonance Imaging (MRI)<br>* 3T Research MRI at 2 weeks and 6 months.<br>Procedure: Blood Draw for Plasma, DNA, Serum, RNA<br>* Blood Draw for Plasma, DNA, Serum, RNA at baseline, in hospital (if applicable), 2 weeks, and 6 months (DNA at baseline only).<br>|
| Brief Assessment<br>• Telephone outcome assessment at 2 weeks, 3 months, 6 months, and 12 months. | Behavioral: Phone Outcome Assessment<br>* NIH Flexible Outcome Assessment Battery Framework Measures by Phone at 2 Weeks, 3 Months, 6 Months, and 12 Months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glasgow Outcome Scale - Extended (GOS-E) | The Glasgow Outcome Scale - Extended (GOS-E) is the current gold standard of outcome for TBI. | 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3T Brain Structural and Functional Magnetic Resonance Imaging (MRI) | Sagittal 3D T1 MPRAGE/IR-SPGR Sagittal 3D T2* GRE Axial Diffusion Tensor Imaging (DTI) Axial Resting State Functional MRI (fMRI) Sagittal 3D T2-FLAIR Sagittal 3D T2 | 2 Weeks | 
| Blood Specimen for Analysis of Biomarkers and Genetics | 6.0ml blood for plasma and DNA 6.0ml blood for serum 2.5ml blood for RNA | Baseline Visit (In-Hospital) | 
| TRACK-TBI Flexible Outcome Assessment Battery Framework (Composite Measure) | Abbreviated Battery GOS-E Confusion Assessment Protocol - Cognitive (CAP-COG) Coma Recovery Scale Revised (CRS-R) Comprehensive Assessment Battery GOS-E Expanded Disability Rating Scale (E-DRS-PI) Rey Auditory Verbal Learning Test (RAVLT) Trail Making Test (TMT) Wechsler Adult Intelligence Scale IV (WAIS) Brief Test of Adult Cognition by Telephone (BTACT) Rivermead Post-Concussion Symptoms Questionnaire Pain Intensity and Interference Instruments (PROMIS-PAIN) Insomnia Severity Index (ISI) Quality of Life After Brain Injury Overall Scale (QOLIBRI-OS) Mayo-Portland Adaptability Inventory - Participation (MPAI-PART) Satisfaction with Life Scale (SWLS) 12-Item Short Form Survey (SF-12) Alcohol Use Disorders Identification Test 3-Item (AUDIT-C) 3-Item Drug Use Interview Post-Traumatic Stress Disorder Checklist 5 (PCL-5) Brief Symptom Inventory 18 (BSI18) Participant Health Questionnaire 9 (PHQ-9) | 2 Weeks | 
| TRACK-TBI Flexible Outcome Assessment Battery Framework (Composite Measure) | Abbreviated Battery GOS-E Confusion Assessment Protocol - Cognitive (CAP-COG) Coma Recovery Scale Revised (CRS-R) Comprehensive Assessment Battery GOS-E Expanded Disability Rating Scale (E-DRS-PI) Rey Auditory Verbal Learning Test (RAVLT) Trail Making Test (TMT) Wechsler Adult Intelligence Scale IV (WAIS) Brief Test of Adult Cognition by Telephone (BTACT) Rivermead Post-Concussion Symptoms Questionnaire Pain Intensity and Interference Instruments (PROMIS-PAIN) Insomnia Severity Index (ISI) Quality of Life After Brain Injury Overall Scale (QOLIBRI-OS) Mayo-Portland Adaptability Inventory - Participation (MPAI-PART) Satisfaction with Life Scale (SWLS) 12-Item Short Form Survey (SF-12) Alcohol Use Disorders Identification Test 3-Item (AUDIT-C) 3-Item Drug Use Interview Post-Traumatic Stress Disorder Checklist 5 (PCL-5) Brief Symptom Inventory 18 (BSI18) Participant Health Questionnaire 9 (PHQ-9) | 3 Months | 
| TRACK-TBI Flexible Outcome Assessment Battery Framework (Composite Measure) | Abbreviated Battery GOS-E Confusion Assessment Protocol - Cognitive (CAP-COG) Coma Recovery Scale Revised (CRS-R) Comprehensive Assessment Battery GOS-E Expanded Disability Rating Scale (E-DRS-PI) Rey Auditory Verbal Learning Test (RAVLT) Trail Making Test (TMT) Wechsler Adult Intelligence Scale IV (WAIS) Brief Test of Adult Cognition by Telephone (BTACT) Rivermead Post-Concussion Symptoms Questionnaire Pain Intensity and Interference Instruments (PROMIS-PAIN) Insomnia Severity Index (ISI) Quality of Life After Brain Injury Overall Scale (QOLIBRI-OS) Mayo-Portland Adaptability Inventory - Participation (MPAI-PART) Satisfaction with Life Scale (SWLS) 12-Item Short Form Survey (SF-12) Alcohol Use Disorders Identification Test 3-Item (AUDIT-C) 3-Item Drug Use Interview Post-Traumatic Stress Disorder Checklist 5 (PCL-5) Brief Symptom Inventory 18 (BSI18) Participant Health Questionnaire 9 (PHQ-9) | 12 Months | 
| 3T Brain Structural and Functional Magnetic Resonance Imaging (MRI) | Sagittal 3D T1 MPRAGE/IR-SPGR Sagittal 3D T2* GRE Axial Diffusion Tensor Imaging (DTI) Axial Resting State Functional MRI (fMRI) Sagittal 3D T2-FLAIR Sagittal 3D T2 | 6 Months | 
| Blood Specimen for Analysis of Biomarkers and Genetics | 6.0ml blood for plasma 6.0ml blood for serum 2.5ml blood for RNA | 2 Weeks | 
| Blood Specimen for Analysis of Biomarkers and Genetics | 6.0ml blood for plasma 6.0ml blood for serum 2.5ml blood for RNA | 6 Months | 
| TRACK-TBI Flexible Outcome Assessment Battery Framework (Composite Measure) | Abbreviated Battery GOS-E Confusion Assessment Protocol - Cognitive (CAP-COG) Coma Recovery Scale Revised (CRS-R) Comprehensive Assessment Battery GOS-E Expanded Disability Rating Scale (E-DRS-PI) Rey Auditory Verbal Learning Test (RAVLT) Trail Making Test (TMT) Wechsler Adult Intelligence Scale IV (WAIS) Brief Test of Adult Cognition by Telephone (BTACT) Rivermead Post-Concussion Symptoms Questionnaire Pain Intensity and Interference Instruments (PROMIS-PAIN) Insomnia Severity Index (ISI) Quality of Life After Brain Injury Overall Scale (QOLIBRI-OS) Mayo-Portland Adaptability Inventory - Participation (MPAI-PART) Satisfaction with Life Scale (SWLS) 12-Item Short Form Survey (SF-12) Alcohol Use Disorders Identification Test 3-Item (AUDIT-C) 3-Item Drug Use Interview Post-Traumatic Stress Disorder Checklist 5 (PCL-5) Brief Symptom Inventory 18 (BSI18) Participant Health Questionnaire 9 (PHQ-9) | 6 Months | 

 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, Comparative Effectiveness Research