BA150793: Dose Optimization of Valproic Acid in a Swine Model of Traumatic Brain Injury, Hemorrhage, and Poly-Trauma, with the Initiation of a Clinical Trial

Injuries kill more young Americans than all other diseases combined. Hemorrhage and traumatic brain injury (TBI) are the leading causes of mortality, and they are especially lethal in combination. TBI affects 1.7 million Americans each year, and it is considered the “signature injury” of the current military conflicts. Over the last 12 years, we have established that early administration (single dose) of a commonly used anti-seizure drug, valproic acid (VPA), can activate numerous pro-survival cellular mechanisms, attenuate organ injury, and improve outcomes. To be effective, this drug has to be given in much larger doses than what has been approved for clinical practice. Therefore, we are performing an FDA approved, DoD funded, phase I clinical trial to determine the maximum safe dose in humans (healthy subjects and patients in hemorrhagic shock). We have also obtained funding for a phase 2/3 trial in patients with hemorrhagic shock. Although, the initial FDA application excluded TBI, recent pre-clinical data shows that VPA treatment is extremely effective in decreasing the brain lesion size, minimizing the neurological impairment, and speeding up the recovery. Due to concerns related to drug toxicity it is important to establish the optimal (lowest effective) dose of VPA that can improve survival and protect the brain.