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In this article, we review past and current experience in clinical trials of traumatic brain injuries (TBIs), we discuss limitations and challenges, and we summarize current directions. The focus is on severe and moderate TBIs. A systematic literature search of the years from 1980 to 2009 revealed 27 large phase III trials in TBI; we were aware of a further 6 unpublished trials. Analysis of these 33 trials yielded interesting observations: There was a peak incidence of trial initiations that occurred in the mid-1990s with a sharp decline during the period from 2000 to 2004. Most trials that reported a significant treatment effect were studies on a therapeutic strategy (e.g., decompressive craniectomy, hypothermia), and these were single-center studies. Increasingly, studies have been shifting toward the Far East. The currently existing trial registries permit insight into ongoing or recently conducted trials. Compared with the past decade, the number of studies on neuroprotective agents taken forward into efficacy-oriented studies is low. In contrast, the number of studies on therapeutic strategies appears to be increasing again. The disappointing results in trials on neuroprotective agents in TBI have led to a critical reappraisal of clinical trial methodology. This has resulted in recommendations for preclinical workup and has triggered extensive analysis on approaches to improve the design and analysis of clinical trials in TBI. An interagency initiative toward standardization on selection and coding of data elements across the broad spectrum of TBI is ongoing, and will facilitate comparison of research findings across studies and encourage high-quality meta-analysis of individual patient data in the future., (Copyright 2010 The American Society for Experimental NeuroTherapeutics, Inc. Published by Elsevier Inc. All rights reserved.)

Clinical trials in traumatic brain injury (TBI) pose complex methodological challenges, largely related to the heterogeneity of the population. The International Mission on Prognosis and Clinical Trial Design in TBI study group has explored approaches for dealing with this heterogeneity with the aim to optimize clinical trials in TBI. Extensive prognostic analyses and simulation studies were conducted on individual patient data from eight trials and three observational studies. Here, we integrate the results of these studies into the International Mission on Prognosis and Clinical Trial Design in TBI recommendations for design and analysis of trials in TBI: Details of the major baseline prognostic characteristics should be provided in every report on a TBI study; in trials they should be differentiated per treatment group. We also advocate the reporting of the baseline prognostic risk as determined by validated prognostic models. Inclusion criteria should be as broad as is compatible with the current understanding of the mechanisms of action of the intervention being evaluated. This will maximize recruitment rates and enhance the generalizability of the results. The statistical analysis should incorporate prespecified covariate adjustment to mitigate the effects of the heterogeneity. The statistical analysis should use an ordinal approach, based on either sliding dichotomy or proportional odds methodology. Broad inclusion criteria, prespecified covariate adjustment, and an ordinal analysis will promote an efficient trial, yielding gains in statistical efficiency of more than 40%. This corresponds to being able to detect a 7% treatment effect with the same number of patients needed to demonstrate a 10% difference with an unadjusted analysis based on the dichotomized Glasgow outcome scale., (Copyright 2010 The American Society for Experimental NeuroTherapeutics, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Heterogeneity of patients is a common problem in randomized controlled trials (RCTs) in various fields of clinical research. We aimed to investigate the potential benefits of different approaches for dealing with heterogeneity in a case study on traumatic brain injury (TBI)., Design and Setting: Statistical modeling studies in three surveys and six randomized controlled trials., Patients: Individual patient data (n = 8033) from the IMPACT database., Interventions: We investigated the statistical power and efficiency of randomized controlled trials (RCTs) in relation to (1) selection according to baseline characteristics, (2) prognostic targeting (i.e., excluding those with a relatively extreme prognosis), and (3) covariate-adjusted analysis. Statistical power was expressed as the required sample size for obtaining 80% power and efficiency as the relative change in study duration, reflecting both gains in power and adverse effects on recruitment. Uniform and targeted treatment effects were simulated for 6 month unfavorable outcome., Results: For a uniform treatment effect, selection resulted ina sample size reduction of 33% in the surveys and 5% in the RCTs, but decreased recruitment by 65% and 41%, respectively. Hence, the relative study duration was prolonged (surveys: 95%; RCTs: 60%). Prognostic targeting resulted in sample size reductions of 28% and 17%, and increased relative study duration by 5% in surveys and 11% in the RCTs. Covariate adjustment reduced sample sizes by 30% and 16%, respectively, and did not affect recruitment. For a targeted treatment effect, the sample size reductions by selection (surveys: 47%; RCTs: 20%) and prognostic targeting (surveys: 49%; RCTs: 41%) were larger and adverse effects on recruitment smaller., Conclusions: The benefits of selection and prognostic targeting in terms of statistical power are reversed by adverse effects on recruitment. Covariate adjusted analysis in a broadly selected group of patients is advisable if a uniform treatment effect is assumed, since there is no decrease in recruitment.

Substantial heterogeneity exists among patients who suffer from traumatic brain injury (TBI). Strict enrollment criteria may diminish heterogeneity in randomized controlled trials (RCTs), but will also decrease recruitment and may affect the outcome distribution. The aim of this study was to investigate the influences of commonly used enrollment criteria for RCTs in TBI on potential recruitment and on outcome distribution. We used individual patient data from the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) database, including six therapeutic phase III RCTs (n = 5816) and three surveys (n = 2217) in TBI. The primary outcome was the Glasgow Outcome Scale (GOS) at 6 months after injury, which we dichotomized as favorable/unfavorable. We investigated the influences of commonly used enrollment criteria on recruitment and outcome distribution: time window between injury and admission to study hospital or= 1 reactive pupil; motor score > 1; Glasgow Coma Scale