Introduction: None of the multi-centre phase III randomized controlled trials (RCTs) performed in TBI have convincingly demonstrated efficacy. Problems in clinical trial design and analysis may have contributed to these failures. Clinical trials in the TBI population pose several complicated methodological challenges, related especially to the heterogeneity of the population. In this paper we examine the issue of heterogeneity within the IMPACT (International Mission on Prognosis and Clinical Trial design in TBI) database and investigate the application of conventional and innovative methods for the statistical analysis of trials in TBI.
Methods and results: Simulation studies in the IMPACT database (N = 9205) showed substantial gains in efficiency with covariate adjustment. Adjusting for 7 important predictors yielded up to a 28% potential reduction in trial size. Ongoing analyses on the potential benefit of ordinal analysis, such as proportional odds and sliding dichotomy, gave promising results with even larger potential reductions in trial size.
Conclusion: The statistical power of RCTs in TBI can be considerably increased by applying covariate adjustment and by ordinal analysis methods of the GOS. These methods need to be considered for optimizing future TBI trials.