Clinical Trials for Traumatic Brain Injury: The Road Traveled and Development of New Pathways

ABSTRACT

Therapeutic clinical trials for the treatment of traumatic brain injury (TBI) have consumed medical and financial resources with few positive results. Current arguments as to why so many trials failed include heterogeneity in the TBI population, delay in instituting therapy, poor penetration of the brain with pharmacological agents, and a lack of understanding regarding the pathophysiological mechanisms involved. This article examines the major trials that have failed, possible reasons for their failure, and possible modifications to improve future TBI trials.

KEYWORDS

Brain - clinical trial - trauma

REFERENCES

• 1 Becker D P, Miller J D, Ward J D, Greenberg R P, Young H F, Sakalas R. The outcome from severe head injury with early diagnosis and intensive management.  J Neurosurg . 1977;  47 491-502
• 2 Lieberman D M, Matz P G, Rosegay H. History of the strain gauge in measurement of the intracranial pressure: from engineers to physiologists and clinicians.  J Trauma . 2002;  52 172-178
• 3 Guidelines authors. Guidelines for the management of severe traumatic brain injury.  J Neurotrauma . 2000;  17 451-554
• 4 Narayan R K, Michel M E, Ansell B. et al . Clinical trials in head injury.  J Neurotrauma . 2002;  19 503-557
• 5 Lewen A, Matz P, Chan P H. Free radical pathways in CNS injury.  J Neurotrauma . 2000;  17 871-890
• 6 Muizelaar J P, Marmarou A, Young H F. et al . Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase: a phase II trial.  J Neurosurg . 1993;  78 375-382
• 7 Young B, Runge J W, Waxman K S. et al . Effects of pegorgotein on neurologic outcome of patients with severe head injury: a multicenter, randomized controlled trial.  JAMA . 1996;  276 538-543
• 8 Marshall L F, Maas A I, Marshall S B. et al . A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury.  J Neurosurg . 1998;  89 519-525
• 9 Teasdale G, Bailey I, Bell A. et al . The effect of nimodipine on outcome after head injury: a prospective randomized control trial. The British/Finnish Co-operative Head Injury Trial Group.  Acta Neurochir Suppl (Wien) . 1990;  51 315-316
• 10 Murray G D, Teasdale G M, Schmitz H. Nimodipine in traumatic subarachnoid haemorrhage: a re-analysis of the HIT I and HIT II trials.  Acta Neurochir (Wien) . 1996;  138 1163-1167
• 11 Langham J, Goldfrad C, Teasdale G, Shaw D, Rowan K. Calcium channel blockers for acute traumatic brain injury.  Cochrane Database Syst Rev . 2000;  2 CD000565
• 12 Lundberg N. Continuous recording and control of ventricular fluid pressure in neurosurgical practice.  Acta Psychiatr Neurol . 1960;  S149 7-193
• 13 Marion D W, Penrod L E, Kelsey S F. et al . Treatment of traumatic brain injury with moderate hypothermia.  N Engl J Med . 1997;  336 540-546
• 14 Clifton G L, Miller E R, Choi S C. et al . Lack of effect of induction of hypothermia after acute brain injury.  N Engl J Med . 2001;  344 556-563
• 15 Bullock R, Zauner A, Woodward J J. et al . Factors affecting excitatory amino acid release following severe human head injury.  J Neurosurg . 1998;  89 507-518
• 16 Morris G F, Bullock R, Marshall S B, Marmarou A, Maas A, Marshall L F. Failure of the competitive N-methyl-D-aspartate antagonist selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. The Selfotel Investigators.  J Neurosurg . 1999;  91 737-743
• 17 Shohami E, Novikov M, Bass R. Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat.  Brain Res . 1995;  674 55-62
• 18 Shohami E, Gallily R, Mechoulam R, Bass R, Ben-Hur T. Cytokine production in the brain following closed head injury: dexanabinol(HU-211) is a novel TNF-alpha inhibitor and an effective neuroprotectant.  J Neuroimmunol . 1997;  72 169-177
• 19 Knoller N, Levi L, Shoshan I. et al . Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial.  Crit Care Med . 2002;  30 548-554
• 20 Choi S C, Bullock R. Design and statistical issues in multicenter trials of severe head injury.  Neurol Res . 2001;  23 190-192
• 21 Dickinson K, Bunn F, Wentz R, Edwards P, Roberts I. Size and quality of randomised controlled trials in head injury: review of published studies.  BMJ . 2000;  320 1308-1311
• 22 Guidelines for the Pre-Hospital Management of Traumatic Brain Injury. New York: Brain Trauma Foundation 2000
• 23 Choi S C, Marmarou A, Bullock R, Nichols J S, Wei X, Pitts L H. Primary end points in phase III clinical trials of severe head trauma: DRS versus GOS. The American Brain Injury Consortium Study Group.  J Neurotrauma . 1998;  15 771-776
• 24 Teasdale G, Pettigrew L E, Wilson J T, Murray G, Jennett B. Analyzing outcome of treatment of severe head injury: a review and update on advancing the use of the Glasgow Outcome Scale.  J Neurotrauma . 1998;  15 587-597
• 25 Tooth L. Use of sequential medical trials in rehabilitation research.  Am J Phys Med Rehabil . 1999;  78 87-97