Posted November 22, 2016
Patrick M. Kochanek, MD, University of Pittsburgh (Overall PI)

Traumatic Brain Injury (TBI) is a leading cause of death and morbidity among Warfighters who served in Operation Iraqi Freedom. This is largely due to the emergence of blast-injury from attacks with improvised explosive devices, the important role of ballistic injury, and other factors. The pathology resulting from these insults is complex, spanning the spectrum from mild to severe TBI, and is often complicated by other factors, including hemorrhagic shock. Non-theatre TBI is also of significant importance across the DoD. Although current therapy for severe TBI includes supportive care, brain-oriented therapy is limited to approaches targeting intracranial pressure. There is also no current therapy for mild TBI, which is a significant source of morbidity and may be linked to post-traumatic stress disorder (PTSD). There is an urgent need for new therapies for those with TBI that are expressly designed to reduce brain swelling, hypoperfusion, axonal injury, neuronal death, cognitive dysfunction, and PTSD.

The Operation Brain Trauma Therapy (OBTT) Consortium was founded to address this pressing need, with support from a JPC-6 FY13 Advanced Technology/Therapeutic Development Award. OBTT represents a unique collaboration among seven of the top experimental TBI centers in the world, combining their expertise to identify and bring forward new treatments for TBI. Member institutions span the military and civilian academic centers in partnership with industry, including the Safar Center for Resuscitation Research at the University of Pittsburgh School of Medicine; the Miami Project to Cure Paralysis at the University of Miami School of Medicine; the Neuroprotection Program at Walter Reed Army Institute of Research; Virginia Commonwealth University; Banyan Biomarkers, Inc.; the University of Florida; and Messina University. This group brings its unprecedented expertise in experimental TBI research and all of the necessary tools for preclinical drug screening and biomarker development and evaluation to bear for the benefit of the Warfighter suffering from TBI.

Since its founding, OBTT has been highly successful and productive in advancing new treatments for TBI. OBTT uses a two-tier screening process to rapidly evaluate the potential of new drugs. In Tier A, OBTT uses established models of TBI in rats to screen the potential new therapies, using a standard battery of tests. Those that perform well advance to Tier B, in which more advanced tests are performed in rats. In each tier, biomarkers of TBI are also evaluated. The most promising agent each year from Tier B advances to secondary screening in micropigs. To date, OBTT has tested nine therapies across three rodent models, with over 5,000 individual biomarker assessments. Two of these drugs, levetiracetam and glibenclamide, have shown promising effects in one or more of the TBI rat models; levetiracetam was identified as the most promising therapy to date, and it has been advanced to testing in micropigs. Glibenclamide has shown promise specifically in contusions and might represent an excellent candidate for a precision medicine approach in patients specifically with cerebral contusions.

OBTT's efforts have garnered national and international acclaim and exposure. In March 2016, a total of eight manuscripts describing the results of the first five therapies tested by OBTT were published together as a special issue of the Journal of Neurotrauma. OBTT was also mentioned in the New England Journal of Medicine as an important tool for the future of the field because it identifies promising TBI drugs for testing in clinical trials. In addition, data from OBTT on rigorous pre-clinical testing across three experimental models on two biomarkers, GFAP and UCH-L1, were very favorably reviewed by the FDA in the applications for ultimate clinical use of these markers as TBI drug development tools. The OBTT project was cited in a published response to an FDA Request for Information on TBI biomarkers (Federal Register Number: 2015-02976). Finally, promising data are being observed by OBTT in exploratory studies with the more novel serum biomarker phospho-neurofilament-heavy (pNF-H).

The current lack of an effective therapy for TBI is a critical problem facing the Warfighter, and the work of OBTT in developing new treatment options is of considerable importance for those who are injured. Both of the promising drugs identified to date have favorable safety profiles and have already been used clinically; OBTT envisions their seamless transition to human clinical trials coupled to effective targeted engagement serum biomarker use. In addition, a 10th candidate therapy (minocycline) has recently completed testing and an 11th drug, E-64d, has begun testing, as OBTT continues to achieve its mission.

Publicaions:

Journal of Neurotrauma Vol 23, Number 6 March 15, 2016 [S1-S8 below].

S1. Kochanek PM, Bramlett HM, Dixon CE, et al. Operation Brain Trauma Therapy: Approach to modeling therapy evaluation, drug selection, and biomarker assessments, for a multi-center pre-clinical drug screening consortium for acute therapies in severe traumatic brain injury. J Neurotrauma 33:513-522.

S2. Shear DA, Dixon CE, Bramlett HM, et al. Operation Brain Trauma Therapy: Nicotinamide treatment in traumatic brain injury. J Neurotrauma 33:523-537.

S3. Bramlett HM, Dietrich WD, Dixon CE, et al. Operation Brain Trauma Therapy: Erythropoietin treatment in traumatic brain injury. J Neurotrauma 33:538-552.

S4. Dixon CE, Bramlett HM, Dietrich WD, et al. Operation Brain Trauma Therapy: Cyclosporine treatment in traumatic brain injury. J Neurotrauma 33:553-566.

S5. Mountney A, Bramlett HM, Dixon CE, et al. Operation Brain Trauma Therapy: Simvastatin treatment in traumatic brain injury. J Neurotrauma 33:567-580.

S6. Browning M, Shear DA, Bramlett HM, et al. Operation Brain TraumaTherapy: Levetiracetam treatment in traumatic brain injury. J Neurotrauma 33:581-594.

S7. Mondello S, Shear DA, Bramlett HM, et al. Operation Brain Trauma Therapy: Insight into preclinical models of traumatic brain injury using circulating brain damage biomarkers. J Neurotrauma 33:595-605.

S8. Kochanek PM, Bramlett HM, Shear DA, et al. Operation Brain Trauma Therapy: Synthesis of findings, current investigations, and future directions. J Neurotrauma 33:606-614.

Wright DW, Yeatts SD, Silvergleit R, et al. 2014. Very early administration of progesterone for acute traumatic brain injury. New Engl J Med 371:2457-2466.

Comment:

Wang K. et al., TRACK-TBI and TED Team Response to FDA Biomarker RFI (DOCKET NO: FDA-2014-N-2187; Federal Register Number: 2015-02976). Available at: http://www.regulations.gov/#!documentDetail;D=FDA-2014-N-2187-0015 [Accessed April 2016].

Link:

Public and Technical Abstracts: Operation Brain Trauma Therapy Extended Studies

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