High expectations of new treatments, but disappointing trials

TBI is a complex and heterogeneous disease, in which the primary damage initiates a cascade of events, leading to secondary brain damage, and rendering the brain more vulnerable to additional insults (Maas, 2000; Maas et al, 1999). The past decade has been characterized by great advances in our understanding of pathophysiologic processes causing secondary brain damage (Teasdale and Graham, 1998; Marshall, 2000), and basic research has resulted in the development of many promising neuroprotective agents aimed at ameliorating such mechanisms. Many of these pre-clinical studies showed a high potential for clinical benefit. Agents carried forward into Phase III clinical trials include corticosteroids, free radical scavengers [e.g. polyethylene glycol-conjugated bovine superoxide dismutase (PEGSOD) and the aminosteroid Tirilazad mesylate], calcium channel blockers (e.g. Nimodipine) and various competitive and non-competitive glutamate N-Methyl-D-aspartate (NMDA) receptor antagonists. Non-pharmaceutical trials have focused on the use of hypothermia and evaluation of a CBF-targeted approach versus an ICP-directed approach (Robertson et al, 1999).

Unfortunately, the great expectations for neuroprotection were not realised on clinical testing. None of the phase III randomized clinical trials in severe and moderate traumatic brain injury (TBI) succeeded to convincingly demonstrate efficacy of new therapies with sufficient generalizibilty. This is of concern, particularly as problems in clinical trial design and analysis may have contributed to this failure. Clinical trials in the TBI-population pose several complicated methodological challenges, related to the heterogeneity of the population, outcome assessment and design issues.