ISOBOLIC COMBINATION DRUG THERAPY DEVELOPMENT FOR TBI

In the past 20 years, numerous Phase II/Phase III clinical trials for moderate/severe TBI have failed to show clinically significant neuroprotective efficacy, despite a plethora of promising pre-clinical evidence from TBI animal models. In fact, the most recent phase III clinical trial of progesterone for treatment of mild to severe TBI was recently halted due to futility. One major reason cited for these disappointing outcomes is that single-drug or monotherapy approaches that target single or limited mechanisms are simply not adequate to address the complex and dynamic milieu of the injured brain. In recognition of the limitations of the monotherapy approach to treating TBI, increased attention is now being directed toward developing combination therapeutic strategies. This issue was addressed by a panel of TBI experts who came to the consensus that the heterogeneity of TBI provides a strong rationale for the hypothesis that combination therapies will improve clinical outcomes compared to current single-agent interventions. The consensus called for a revisiting of the most promising neuroprotective agents and challenged the Neurotrauma research community to develop step-by-step strategies for pre-clinical and clinical research on combination therapies designed to augment the efficacy of promising monotherapies with the potential to improve clinical outcome.