Clinical Trials in Traumatic Brain Injury: Past Experience and Current Developments

Abstract

Summary: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search of the years from 1980 to 2009 revealed 27 large phase III trials in TBI; we were aware of a further 6 unpublished trials.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.

Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury

“…S6); however, in the vast majority (up to 90%) of TBI incidents in humans, swelling and oedema are confined to the skull in nonpenetrating injuries 36 . We sought to use a focal injury, the mouse cortical cold injury model, which has previously been used extensively to study the dynamic of cerebral oedema formation [37][38][39] . This model has been shown to cause changes in caveolin-1, occludin and claudin-5 expression within the lesion site at various time points post-injury and highlights the dynamic changes that occur with respect to the BBB post-neuronal injury 20 .…”

Global neurotrauma research challenges and opportunities

“…Most of these evidence-based recommendations are best applied in well-funded and well-equipped neurosurgical or neurotrauma centres [15][16][17] . The recent Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST Trip) trial was based on standard recommendations for randomized clinical trials in high-income countries [18][19][20][21][22] . Results were far from expected because advanced monitoring tools used to guide treatments in high-income countries were not as successful in LMICs, and discussion within the global neurotrauma scientific community emerged after the publication of this study [23][24][25][26][27] .…”

Challenges Enrolling Children Into Traumatic Brain Injury Trials: An Observational Study

“…10 In the CRASH I trial (which included children older than 16 years of age) sites which had to obtain written informed consent took significantly longer to randomize patients and ultimately to administer study drug (3 hours vs. 4 hours). 31,32 Our study also showed substantial heterogeneity of intracranial injuries among children with moderate-tosevere TBIs. The implications of this may be important, as certain interventions may target specific types of intracranial injuries.…”