Traumatic Brain Injury (TBI) is a major cause of death and disability both in the United States and worldwide. This proposal focuses on persons with severe TBI (those with prolonged unresponsiveness [Glasgow Coma Scale < 8]). Severe TBI affects nearly 27,000 persons in the United States each year. These patients experience high mortality and require sophisticated care in intensive care units estimated at up to $244 billion dollars each year. There are no therapeutic agents that have been shown to improve outcomes from severe traumatic brain injury (TBI). Critical barriers to progress in developing treatments for severe TBI are the lack of: 1) monitoring biomarkers for assessing individual patient response to treatment; 2) predictive biomarkers for identifying patients likely to benefit from a promising intervention. Currently, clinical examination remains the fundamental tool for monitoring severe TBI patients and for subject selection in clinical trials. However, these patients are typically intubated and sedated, limiting the utility of clinical examinations. Validated monitoring and predictive biomarkers will allow titration of the dose of promising therapeutics to individual subject response, as well as make clinical trials more efficient by enabling the enrollment of subjects likely to benefit. Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and high sensitivity c-reactive protein (hsCRP) are promising biomarkers that may be useful as 1) monitoring biomarkers; 2) predictive biomarkers in severe TBI trials. Although the biological rationale supporting their use is strong, significant knowledge gaps remain. To address these gaps in knowledge, we propose an ancillary observational study leveraging an ongoing severe TBI clinical trial that is not funded to collect biospecimen. The Hyperbaric Oxygen in Brain Injury Treatment (HOBIT) trial, a phase II randomized control clinical trial that seeks to determine the dose of hyperbaric oxygen therapy (HBOT) that that has the highest likelihood of demonstrating efficacy in a phase III trial. The proposed study will: 1) validate the accuracy of candidate monitoring biomarkers for predicting clinical outcome; 2) determine the treatment effect of different doses of HBOT on candidate monitoring biomarkers; and 3) determine whether there is a biomarker defined subset of severe TBI that responds favorably to HBOT. This proposal will: 1) inform a go/no-go decision for a phase III trial of HBOT by providing adjunctive evidence of the effect of HBOT on key biological pathways through which HBOT is hypothesized to affect outcome; 2) provide evidence to support further study of the first monitoring biomarkers of severe TBI; 3) increase the likelihood of success of a phase III trial by identifying the sub-population of severe TBI likely to benefit from HBOT; 4) create a repository of TBI biospecimen which may be accessed by other investigators.

Public Health Relevance

Traumatic brain injury (TBI) remains a leading cause of death and disability both in the United States and worldwide. In order to improve neurologic recovery from TBI, novel methods are needed for monitoring how well individual patients respond to neuroprotective treatment. The proposed work will examine blood levels of proteins that are released into circulation when brain cells die and determine how the levels of these protein are influenced by an experimental treatment for neuroprotection (hyperbaric oxygen).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS114251-01A1S1
Application #
10359402
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Mendoza-Puccini, Maria Carolina
Project Start
2020-09-15
Project End
2023-08-31
Budget Start
2020-12-15
Budget End
2021-08-31
Support Year
1
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Emergency Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109