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. 2010 Jan;7(1):115–126. doi: 10.1016/j.nurt.2009.10.022

Clinical trials in traumatic brain injury: Past experience and current developments

Andrew I R Maas 1,✉, Bob Roozenbeek 1,2, Geoffrey T Manley 3
PMCID: PMC5084118  PMID: 20129503

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search of the years from 1980 to 2009 revealed 27 large phase III trials in TBI; we were aware of a further 6 unpublished trials.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

Key Words: Traumatic brain injury, randomized controlled trials, neuroprotection, methodology, standardization

References

  • 1.Maas AI, Steyerberg EW, Murray GD, et al. Why have recent trials of neuroprotective agents in head injury failed to show convincing efficacy? A pragmatic analysis and theoretical considerations. Neurosurgery. 1999;44:1286–1298. doi: 10.1097/00006123-199906000-00076. [DOI] [PubMed] [Google Scholar]
  • 2.Narayan RK, Michel ME, Ansell B, et al. Clinical trials in head injury. J Neurotrauma. 2002;19:503–557. doi: 10.1089/089771502753754037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Maas AIR, Marmarou A, Murray GD, Teasdale GM, Steyerberg EW. Prognosis and clinical trial design in traumatic brain injury: the IMPACT Study. J Neurotrauma. 2007;24:232–238. doi: 10.1089/neu.2006.0024. [DOI] [PubMed] [Google Scholar]
  • 4.Maas AIR, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurology. 2008;7:728–741. doi: 10.1016/S1474-4422(08)70164-9. [DOI] [PubMed] [Google Scholar]
  • 5.Finkelstein EA, Corso PS, Miller TR, et al. The incidence and economic burden of injuries in the United States. New York: Oxford University Press; 2006. [Google Scholar]
  • 6.Servadei F, Murray GD, Penny K, et al. The value of the “worst” computed tomographic scan in clinical studies of moderate and severe head injury. European Brain Injury Consortium. Neurosurgery. 2000;46:70–7. doi: 10.1097/00006123-200001000-00014. [DOI] [PubMed] [Google Scholar]
  • 7.Chang EF, Meeker M, Holland MC. Acute traumatic intraparenchymal hemorrhage: risk factors for progression in the early post-injury period. Neurosurgery. 2006;58:647–656. doi: 10.1227/01.NEU.0000197101.68538.E6. [DOI] [PubMed] [Google Scholar]
  • 8.Oertel M, Kelly DF, McArthur D, et al. Progressive hemorrhage after head trauma: predictors and consequences of the evolving injury. J Neurosurg. 2002;96:109–116. doi: 10.3171/jns.2002.96.1.0109. [DOI] [PubMed] [Google Scholar]
  • 9.Harders A, Kakarieka A, Braakman R. Traumatic subarachnoid hemorrhage and its treatment with nimodipine. German tSAH Study Group. J Neurosurg. 1996;85:82–9. doi: 10.3171/jns.1996.85.1.0082. [DOI] [PubMed] [Google Scholar]
  • 10.Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Critical Care. 2008;12:R61–R61. doi: 10.1186/cc6887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomized placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet. 2005;365:1957–1959. doi: 10.1016/S0140-6736(05)66552-X. [DOI] [PubMed] [Google Scholar]
  • 12.Zhi D, Zhang S, Lin X. Study on therapeutic mechanism and clinical effect of mild hypothermia in patients with severe head injury. Surg Neurol. 2003;59:381–385. doi: 10.1016/S0090-3019(03)00148-4. [DOI] [PubMed] [Google Scholar]
  • 13.Lu LQ, Jiang JY, Yu MK, et al. Standard large trauma craniotomy for severe traumatic brain injury. Chin J Traumatol. 2003;5:302–304. [PubMed] [Google Scholar]
  • 14.Jiang J, Xu W, Li W, et al. Efficacy of standard trauma craniectomy for refractory intracranial hypertension with severe traumatic brain injury: a multicenter, prospective, randomized controlled study. J Neurotr. 2005;22:623–628. doi: 10.1089/neu.2005.22.623. [DOI] [PubMed] [Google Scholar]
  • 15.Jiang JY, Xu W, Li W, et al. Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury. J Cereb Blood Flow Metab. 2006;26:771–776. doi: 10.1038/sj.jcbfm.9600253. [DOI] [PubMed] [Google Scholar]
  • 16.Clifton GL, Choi SC, Miller ER, et al. Intercenter variance in clinical trials of head trauma—experience of the National Acute Brain Injury Study: hypothermia. J Neurosurg. 2001;95:751–755. doi: 10.3171/jns.2001.95.5.0751. [DOI] [PubMed] [Google Scholar]
  • 17.Maas AI, Murray G, Henney H, et al. Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 2006;5:38–45. doi: 10.1016/S1474-4422(05)70253-2. [DOI] [PubMed] [Google Scholar]
  • 18.Bailey I, Bell A, Gray J, et al. A trial of the effect of nimodipine on outcome after head injury. Acta Neurochir (Wien) 1991;110:97–105. doi: 10.1007/BF01400674. [DOI] [PubMed] [Google Scholar]
  • 19.European Study Group A multicenter trial of the efficacy of nimodipine on outcome after severe head injury. The European Study Group on Nimodipine in Severe Head Injury. J Neurosurg. 1994;80:797–804. doi: 10.3171/jns.1994.80.5.0797. [DOI] [PubMed] [Google Scholar]
  • 20.Gramme T, Baethmann A, Kolodziejczyk D, et al. Treatment of patients with severe head injury by triamconolone: a prospective, controlled multicenter clinical trial of 396 cases. Res Exp Med (Berl) 1995;195:217–229. doi: 10.1007/BF02576791. [DOI] [PubMed] [Google Scholar]
  • 21.Young B, Runge JW, Waxman KS, et al. Effects of pegorgotein on neurologic outcome of patients with severe head injury. A multicenter, randomized controlled trial. JAMA. 1996;276:538–543. doi: 10.1001/jama.276.7.538. [DOI] [PubMed] [Google Scholar]
  • 22.Marmarou A, Nichols J, Burgess J, et al. Effects of bradykinin antagonist Bradycor (Deltibant, CP-1027) in severe traumatic brain injury: results of a multi-center, randomized, placebo-controlled trial. J Neurotr. 1999;16:431–444. doi: 10.1089/neu.1999.16.431. [DOI] [PubMed] [Google Scholar]
  • 23.Yurkewicz L, Weaver J, Bullock MR, Marshall LF. The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury. J Neurotr. 2005;12:1428–1443. doi: 10.1089/neu.2005.22.1428. [DOI] [PubMed] [Google Scholar]
  • 24.Maas AIR, Steyerberg EW, Marmarou A, et al. IMPACT recommendations for improving the design and analysis of clinical trials in moderate to severe traumatic brain injury. Neurotherapeutics. 2010;7:127–134. doi: 10.1016/j.nurt.2009.10.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Marmarou A, Lu J, Butcher I, et al. IMPACT database of traumatic brain injury: design and description. J Neurotrauma. 2007;24:239–250. doi: 10.1089/neu.2006.0036. [DOI] [PubMed] [Google Scholar]
  • 26.Braakman R, Schouten HJA, Blaauw-Van Dishoeck M, Minderhoud JM. Megadose steroids in severe head injury. J Neurosurg. 1983;58:326–330. doi: 10.3171/jns.1983.58.3.0326. [DOI] [PubMed] [Google Scholar]
  • 27.Dearden NM, Gibson JS, McDowall DG, Gibson RM, Cameron MM. Effect of high-dose dexamethasone on outcome from severe head injury. J Neurosurg. 1986;64:81–88. doi: 10.3171/jns.1986.64.1.0081. [DOI] [PubMed] [Google Scholar]
  • 28.Rockswold GL, Ford SE, Anderson DC, Bergman TA, Sherman RE. Results of a prospective randomized trial for treatment of severely brain-injured patients with hyperbaric oxygen. J Neurosurg. 1992;76:929–934. doi: 10.3171/jns.1992.76.6.0929. [DOI] [PubMed] [Google Scholar]
  • 29.Wolf AL, Levi L, Marmarou A, et al. Effect of THAM upon outcome in severe head injury: a randomized prospective clinical trial. J Neurosurg. 1993;78:54–59. doi: 10.3171/jns.1993.78.1.0054. [DOI] [PubMed] [Google Scholar]
  • 30.Gaab MR, Trost HA, Alcantara A, et al. “Ultrahigh” dexamethasone in acute brain injury. Results from a prospective randomized double-blind multicenter trial (GUDHIS). German Ultrahigh Dexamethasone Head Injury Study Group. Zentralbl Neurochir. 1994;55:135–143. [PubMed] [Google Scholar]
  • 31.Marshall LF, Maas AI, Marshall SB, et al. A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg. 1998;89:519–525. doi: 10.3171/jns.1998.89.4.0519. [DOI] [PubMed] [Google Scholar]
  • 32.Robertson CS, Valadka AB, Hannay HJ, et al. Prevention of secondary ischemic insults after severe head injury. Crit Care Med. 1999;27:2086–2095. doi: 10.1097/00003246-199910000-00002. [DOI] [PubMed] [Google Scholar]
  • 33.Morris GF, Bullock R, Bowers Marshall S, et al. 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. J Neurosurg. 1999;91:737–743. doi: 10.3171/jns.1999.91.5.0737. [DOI] [PubMed] [Google Scholar]
  • 34.Cooper DJ, Myles PS, McDermott FT, et al. Prehospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury. JAMA. 2004;291:1350–1357. doi: 10.1001/jama.291.11.1350. [DOI] [PubMed] [Google Scholar]
  • 35.Temkin NR, Anderson GD, Winn HR, et al. Magnesium sulfate for neuroprotection after traumatic brain injury: a randomized controlled study. Lancet Neurol. 2007;6:29–38. doi: 10.1016/S1474-4422(06)70630-5. [DOI] [PubMed] [Google Scholar]
  • 36.Cruz J, Minoja G, Okuchi K. Improving clinical outcomes from acute subdural hematomas with the emergency preoperative administration of high doses of mannitol: a randomized trial. Neurosurg. 2001;49:864–871. doi: 10.1097/00006123-200110000-00016. [DOI] [PubMed] [Google Scholar]
  • 37.Cruz J, Minoja G, Okuchi K. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hermorrhages with abnormal papillary widening: a randomized trial. Neurosurg. 2002;51:628–638. doi: 10.1097/00006123-200209000-00006. [DOI] [PubMed] [Google Scholar]
  • 38.Mazzeo AT, Brophy G, Gilman CB, et al. Safety and tolerability of cyclosporin A in severe traumatic brain injury patients: results from a prospective, randomized trial. J Neurotrauma 2009 Jul 21 [Epub ahead of print]. [DOI] [PMC free article] [PubMed]
  • 39.Roberts I, Smith R, Evans S. Doubts over head injury studies. BMJ. 2007;334:392–394. doi: 10.1136/bmj.39118.480023.BE. [DOI] [PMC free article] [PubMed] [Google Scholar]

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