Injuria Cerebral Traumatica

JOURNAL OF NEUROTRAUMA 26:925–939 (June 2009) ª Mary Ann Liebert, Inc. DOI: 10.1089=neu.2008.0794

Combination Therapies for Traumatic Brain Injury: Prospective Considerations
Susan Margulies,1 Ramona Hicks,2 and The Combination Therapies for Traumatic Brain Injury Workshop Leaders*

Many of life’s failures are people who did not realize how close they were to success when they gave up.—Thomas A. Edison (1847–1931) Abstract

Traumatic brain injury (TBI) initiates a cascade of numerous pathophysiological events that evolve over time. Despite the complexity of TBI, research aimed at therapy development has almost exclusively focused on single therapies, all of which have failed in multicenter clinical trials. Therefore, in February 2008 the National Institute of Neurological Disordersand Stroke, with support from the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, and the Department of Veterans Affairs, convened a workshop to discuss the opportunities and challenges of testing combination therapies for TBI. Workshop participants included clinicians and scientists from a variety of disciplines, institutions, and agencies. Theobjectives of the workshop were to: (1) identify the most promising combinations of therapies for TBI; (2) identify challenges of testing combination therapies in clinical and pre-clinical studies; and (3) propose research methodologies and study designs to overcome these challenges. Several promising combination therapies were discussed, but no one combination was identified as being the mostpromising. Rather, the general recommendation was to combine agents with complementary targets and effects (e.g., mechanisms and time-points), rather than focusing on a single target with multiple agents. In addition, it was recommended that clinical management guidelines be carefully considered when designing pre-clinical studies for therapeutic development. To overcome the challenges of testingcombination therapies it was recommended that statisticians and the U.S. Food and Drug Administration be included in early discussions of experimental design. Furthermore, it was agreed that an efficient and validated screening platform for candidate therapeutics, sensitive and clinically relevant biomarkers and outcome measures, and standardization and data sharing across centers would greatlyfacilitate the development of successful combination therapies for TBI. Overall there was great enthusiasm for working collaboratively to act on these recommendations.
Key words: clinical trials; head injury; injury mechanisms; intervention; in-vitro and in-vivo models

University of Pennsylvania, Philadelphia, Pennsylvania. National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.*Beth Ansel, National Institute of Child Health and Human Development, Bethesda, Maryland; Ross Bullock, University of Miami, Miami, Florida; David Clifford, Washington University School of Medicine, St. Louis, Missouri; Guy Clifton, University of Texas Health Science Center, Houston, Texas; Robin Conwit, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland; Pramod Dash,University of Texas Health Science Center, Houston, Texas; Ramon Diaz-Arrastia, University of Texas Southwestern Medical Center, Dallas, Texas; W. Dalton Dietrich, III, University of Miami, Miami, Florida; Billy Dunn, Food and Drug Administration, Rockville, Maryland, Center for Drug Evaluation and Research, Silver Spring, Maryland; Scott Emerson, University of Washington, Seattle, Washington;Stephanie Fertig, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland; Edward D. Hall, University of Kentucky, Lexington, Kentucky; David Hoyt, University of California, Irvine, California; Scott Janis, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland; Walter Koroshetz, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland;...