Combination Therapies for Traumatic Brain Injury – Prospective Considerations

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 Disorders and 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. The objectives 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 most promising. 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 testing combination 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 greatly facilitate the development of successful combination therapies for TBI. Overall there was great enthusiasm for working collaboratively to act on these recommendations.

Therapy Development for Diffuse Axonal Injury

“…185,188,189 Potentially, hypothermia impedes the progression of TAI, allowing adjunct drug therapy to superimpose protective effects at more delayed time points. Regardless, combinational therapy with hypothermia merits continued investigation.…”

Evaluation of a Combined Treatment Paradigm Consisting of Environmental Enrichment and the 5-HT1A Receptor Agonist Buspirone after Experimental Traumatic Brain Injury

“…The overall lack of translational success has evolved into the current thinking by many in the TBI community that mono-therapies may be insufficient to produce a translatable product, and that a more dedicated effort toward poly-therapies is necessary. Indeed, a National Institutes of Health (NIH) TBI workshop convened to discuss the opportunities and challenges associated with conducting research studies using multiple drug interventions (Margulies et al, 2009). The workshop leaders focused exclusively on the potential for combinatorial pharmacological agents to promote recovery.…”

Effects of Mild Hypothermia Treatment on Rat Hippocampal β-Amyloid Expression Following Traumatic Brain Injury

“…Despite these efforts, mortality for TBI patients in emergency care facilities remains between 25% and 30% (Tu et al, 2012), and no successful Phase III trials of pharmacological agents for TBI have been reported to date (Okonkwo, 2008). Because of the increasing prevalence and high mortality rate of TBI (Margulies and Hicks, 2009), improved early diagnostic methods and treatment strategies for TBI are urgently required in clinical settings, posing a challenge for neurological researchers.…”