Assessment of agents for the treatment of head injury : Problems and pitfalls in trial design

Over the past decade many neuroprotective agents have been developed with the hope of being able to improve outcome in patients with acute cerebral disorders, such as stroke, head injury and subarachnoid haemorrhage. Unfortunately, in the field of head injury none of the phase III trials performed have convincingly demonstrated efficacy in the overall population. A common misconception is that consequently these agents are ineffective. Such has, however, not been proven, and some trials show evidence of efficacy in subgroups of the population studied. The negative results, as reported in the overall population, may in part be caused by specific aspects of the head injury population, as well as by aspects of clinical trial design and analysis. The present manuscript addresses these issues, and critically analyses the relevance of preclinical evidence and pharmacokinetic studies. It appears that decisions about initiating phase III trials in head injury were strongly influenced by experience in related disorders, such as subarachnoid haemorrhage and stroke. The available evidence from experimental studies in the field of head injury is limited and uncertainties exist about whether the pathophysiological mechanisms at which neuroprotective agents were targeted really occurred in all patients studied. Moreover, for many agents, aspects of pharmacokinetics and penetration into the brain were insufficiently investigated before proceeding into phase III trials. The heterogeneity of the head injury population may cause specific problems, such as a risk of imbalances between placebo and treated groups, but also causes problems when a possible treatment effect is evaluated in relation to the prognostic effect present. It is concluded that trials of neuroprotective agents should be targeted first of all to a population in which the mechanism at which the agent is directed is likely to be present, and secondly to a population in which the chances of demonstrating efficacy are realistic, i.e. patients with an intermediate prognosis. The aim in most trials of trying to demonstrate a 10% absolute improvement in favourable outcome in patients with head injury is over-optimistic and unrealistic in relation to the heterogenous patient population. Specific problems incurred by the use of the dichotomised Glasgow Outcome Scale as the primary outcome measure are discussed, and the risk highlighted that even a substantial change in outcome distribution may not be adequately det