Clinical Trials in Head Injury

Abstract

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate signficant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.

Phosphodiesterase‐5 inhibition potentiates cerebrovascular reactivity in chronic traumatic brain injury

“…It is estimated that the prevalence of Americans with chronic TBI‐related disability is 5.3 million 2, 3, 4, 5. The magnitude of this problem has led to extensive pre‐clinical research and clinical trials to improve functional outcomes 6. Despite success in animal models, all Phase III human clinical trials to date have failed 7, 8, 9, 10.…”

“…Despite success in animal models, all Phase III human clinical trials to date have failed 7, 8, 9, 10. Consensus conferences have concluded that biomarkers will be critical for the development of effective TBI therapies targeted at injury‐specific mechanisms 6, 11…”

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

“…In the field of traumatic brain injury (TBI), however, not a single multicenter phase III RCT on neuroprotective agents has convincingly shown benefit. [1][2][3] As a consequence, a sense of disappointment prevails; basic science researchers are increasingly frustrated that their hard and promising work performed under clean experimental conditions does not seem to transfer into the "dirty" clinical situation, and there is some reluctance by pharmaceutical companies to embark on a new high-cost venture in TBI. However, trials conducted so far have not definitively established the lack of possible benefit.…”

The Glasgow Outcome Scale — 40 years of application and refinement

“…The later description of the extended GOS (GOSE) 7 is in the top 25 cited papers on traumatic brain injury (TBI) 8 . The GOS in its original or extended form is recommended as the outcome measure to be used for major trauma and for head injury by, among others, the National Institute of Neurological Disorders and Stroke, the NIH National Institute of Child Health and Human Development TBI Clinical Trials Network and the Department of Health in England [9][10][11] . In the USA, the GOS is the core measure used for outcome research in TBI in the Common Data Elements project 12 .…”