Neurological deterioration as a potential alternative endpoint in human clinical trials of experimental pharmacological agents for treatment of severe traumatic brain injuries. Executive Committee of the International Selfotel Trial.
OBJECTIVE: A recently improved understanding of the pathophysiological features of head injuries has led to the development of new drug therapies. Accurate human clinical trials remain necessary to document the efficacy and safety of new agents. It would be helpful to decrease the time from drug development to clinical use and general availability for drugs found to be effective. Conversely, ineffective agents could be abandoned in a timely fashion. RATIONALE: A new endpoint measure, defined as neuroworsening (NW), is an objective observable event that is identifiable during hospitalization. This may enable the efficacy of drugs to be demonstrated or disproved much earlier than with 6-month outcome assessments. The prospective, double-blind, multicenter trial of the N-methyl-D-aspartate receptor antagonist Selfotel was used to acquire data on the efficacy of NW in predicting neurological outcomes. The 6-month Glasgow Outcome Scale scores, which were the primary endpoints of that trial, were compared with the frequency of NW. NW was an observable event that could be objectively defined after head injuries. Patients who suffered one or more episodes of NW demonstrated significantly higher morbidity and mortality rates than did patients who did not. CONCLUSION: Future trials should consider the use of NW as an outcome measure that can be included with more traditional measures in the study design. If the strong correlation demonstrated between NW and 6-month Glasgow Outcome Scale scores can be prospectively demonstrated in a successful trial, the time to approval of future agents could be decreased.