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9	What are the clinical uses of biomarkers for traumatic brain injury? Improved clinical trial design Improved patient management
10	Improved Clinical Trial Design The Cochrane Library (1999) published six systematic reviews: after more that 200 clinical trials, all therapies were either ineffective or evidence of efficacy remains inconclusive. The recent failure of dexanabinol (Pharmos) highlights this problem. Many companies are reluctant to asses therapies to treat acute CNS injury without appropriate biomarkers (e.g. Merck)
11	Improved clinical trial design Patient A: 35 year old male admitted to the trauma center after a car accident. He hit a light pole while intoxicated with alcohol and marihuana. Treated for shock in the trauma center, including CPR. On arrival to the ICU he is comatose and does not respond to painful stimulation. The principal investigator of a new drug trial for severe TBI wonders if this patient meets inclusion criteria for a phase III trial of a new neuroprotective drug.
12	Clinical Trials of TBI: a challenge for academia
13	Integration of Biomarkers into TBI Clinical Trials: a perspective from industry
14	Challenges to Clinical Trials of TBI Inaccurate assessment of injury magnitude by Glasgow Coma Scale Outcome determined by secondary insults in addition to injury magnitude Need to identify pathophysiological mechanisms of TBI in humans to generate compounds targeted to such mechanisms Outcome measures such as the Glasgow Outcome Scale are insensitive and assessments are delayed (6 months to one year) Need to standardize clinical management as carefully as possible within and across centers
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30	Rat CSF vs. Human CSF αII-SBDP (SBDP150 & SBDP145)
31	SBDP’s in human CSF post-TBI Three centers: UF Gainesville, Jacksonville, Baylor TBI GCS ≤ 8 Management according to the guidelines Monitoring multiple physiological parameters (continuous MAP, ICP, CPP, pBrO₂, Br T, CBF) Collecting CSF and serum samples (daily for 7 d) Severe TBI n = 41 Hydrocephalic controls n = 11
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33	Challenges to Clinical Trials of TBI Inaccurate assessment of injury magnitude by Glasgow Coma Scale Outcome determined by secondary insults in addition to injury magnitude Need to identify pathophysiological mechanisms of TBI in humans to generate compounds targeted to such mechanisms Outcome measures such as the Glasgow Outcome Scale are insensitive and assessments are delayed (6 months to one year) Need to standardize clinical management as carefully as possible within and across centers
34	More rigorous stratification of patients by injury magnitude
35	More rigorous stratification of patients by injury magnitude
36	Challenges to Clinical Trials of TBI Inaccurate assessment of injury magnitude by Glasgow Coma Scale Outcome determined by secondary insults in addition to injury magnitude Need to identify pathophysiological mechanisms of TBI in humans to generate compounds targeted to such mechanisms Outcome measures such as the Glasgow Outcome Scale are insensitive and assessments are delayed (6 months to one year) Need to standardize clinical management as carefully as possible within and across centers
37	Allows stratification of patients by secondary insults
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39	Allows stratification of patients by secondary insults
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41	Challenges to Clinical Trials of TBI Inaccurate assessment of injury magnitude by Glasgow Coma Scale Outcome determined by secondary insults in addition to injury magnitude Need to identify pathophysiological mechanisms of TBI in humans to generate compounds targeted to such mechanisms Outcome measures such as the Glasgow Outcome Scale are insensitive and assessments are delayed (6 months to one year) Need to standardize clinical management as carefully as possible within and across centers
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44	Challenges to Clinical Trials of TBI Inaccurate assessment of injury magnitude by Glasgow Coma Scale Outcome determined by secondary insults in addition to injury magnitude Need to identify pathophysiological mechanisms of TBI in humans to generate compounds targeted to such mechanisms Outcome measures such as the Glasgow Outcome Scale are insensitive and assessments are delayed (6 months to one year) Need to standardize clinical management as carefully as possible within and across centers
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46	Provides early prediction of outcome for sequential design in clinical trials
47	Conclusion Accumulation of αII-SBDP in preclinical studies is reproduced in humans following severe TBI Rodent TBI models can provide useful preclinical tools for evaluation of potential biomarkers for human TBI αII-SBDP can provide useful tools in patient clinical trial design (and patient management) in human TBI
48	Challenges to Clinical Trials of TBI Inaccurate assessment of injury magnitude by Glasgow Coma Scale Outcome determined by secondary insults in addition to injury magnitude Need to identify pathophysiological mechanisms of TBI in humans to generate compounds targeted to such mechanisms Outcome measures such as the Glasgow Outcome Scale are insensitive and assessments are delayed (6 months to one year) Need to standardize clinical management as carefully as possible within and across centers
49	Future directions Refine biomarker outcome prediction Assess role of secondary insults Assess relative contributions of different cell death mechanisms Clarify significant relationships between physiological changes, biomarkers and outcome (WRAIR) Assess utility of biomarkers in other acute brain injury scenarios (SAH, Pediatric TBI)
50	Aneurysmal subarachnoid hemorrhage
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