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Clinical Trials in Head Injury
Open accessAbstract
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 significant 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.
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“Despite preclinical studies providing evidence for successful pharmacologic intervention, more than 30 phase-III clinical trials have failed to improve secondary injury outcome measures after TBI (35–37).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [35]
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Brain tissue oxygen-directed management and outcome in patients with severe traumatic brain injury.
Spiotta, A., Stiefel, M. F., Gracias, V., Garuffe, A. M., Kofke, W., Maloney-Wilensky, E., Troxel, A., Levine, J. M., & le Roux, P. L. (2010) · Journal of Neurosurgery · doi:10.3171/2010.1.jns09506 · Cited by 226
Laird, M. D., Shields, J., Sukumari‐Ramesh, S., Kimbler, D. E., Fessler, R. D., Shakir, B., Youssef, P. P., Yanasak, N. E., Vender, J. R., & Dhandapani, K. M. (2013) · Glia · doi:10.1002/glia.22581 · Cited by 256
“Astrocytic swelling, a characteristic feature of cellular edema, commences within hours of TBI in humans (Ito et al., 1996; Kimelberg, 1992; Narayan et al., 2002) and is associated with increased expression of AQP4 water channels (Badaut et al., 2002; Gunnarson et al., 2008; Nase et al., 2008).”
BackgroundAnti–high mobility group box‐1 antibody therapy for traumatic brain injury
Okuma, Y., Liu, K., Wake, H., Zhang, J., Maruo, T., Date, I., Yoshino, T., Ohtsuka, A., Otani, N., Tomura, S., et al. (2012) · Annals of Neurology · doi:10.1002/ana.23602 · Cited by 236
Experimental strategies to promote spinal cord regeneration—an integrative perspective
Schwab, J. M., Brechtel, K., Mueller, C.-A., Failli, V., Kaps, H.-P., Tuli, S. K., & Schluesener, H. J. (2006) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.12.004 · Cited by 213
Bench-to-bedside review: Apoptosis/programmed cell death triggered by traumatic brain injury
Zhang, X., Chen, Y.-M., Jenkins, L., Kochanek, P., & Clark, R. (2004) · Critical Care · doi:10.1186/cc2950 · Cited by 223
“clinical trials have failed to show benefit from therapeutic strategies proven to be effective in the laboratory [11–13].”
BackgroundSelf-citationFarahvar, A., Gerber, L., Chiu, Y.-L., Carney, N., Härtl, R., & Ghajar, J. (2012) · Journal of Neurosurgery · doi:10.3171/2012.7.jns111816 · Cited by 222
Self-citationAnimal Models of Traumatic Brain Injury and Assessment of Injury Severity
Ma, X., Aravind, A., Pfister, B. J., Chandra, N., & Haorah, J. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1454-5 · Cited by 271
“The prevention of TBI-related neurodegenerative disorders has not been satisfactorily successful despite the number of clinical trials and treatment [18, 19], which was partly attributed to clinical irrelevance of the animal models [20].”
BackgroundBrain tissue oxygen and outcome after severe traumatic brain injury: A systematic review*
Maloney-Wilensky, E., Gracias, V., Itkin, A., Hoffman, K., Bloom, S., Yang, W., Christian, S., & Leroux, P. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181a009f8 · Cited by 220
Foreman, B., Caesar, R., Parks, J. K., Madden, C. J., Gentilello, L., Shafi, S., Carlile, M. C., Harper, C., & Diaz-Arrastia, R. (2007) · Journal of Trauma · doi:10.1097/01.ta.0000229796.14717.3a · Cited by 220
Peri-infarct depolarizations lead to loss of perfusion in ischaemic gyrencephalic cerebral cortex
Strong, A. J., Anderson, P. J., Watts, H. R., Virley, D. J., Lloyd, A., Irving, E. A., Nagafuji, T., Ninomiya, M., Nakamura, H., Dunn, A. K., et al. (2006) · Brain · doi:10.1093/brain/awl392 · Cited by 209
“, 2000) [together with the negative results of many clinical neuroprotection studies largely based on experimental findings in rodent models (Narayan et al., 2002)].”
BackgroundLu, D., Goussev, A. V., Chen, J., Pannu, P., Li, Y., Mahmood, A., & Chopp, M. (2004) · Journal of Neurotrauma · doi:10.1089/089771504772695913 · Cited by 198
“HMG-CoA reductase inhibition has an effect on angiogenesis that is mainly independent of its effects on blood cholesterol (Narayan et al., 2002).”
MSCs-Derived Exosomes and Neuroinflammation, Neurogenesis and Therapy of Traumatic Brain Injury
Yang, Y., Ye, Y., Su, X., He, J., Bai, W., & He, X. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00055 · Cited by 237
“Until recently, no clinical trials have identified effective pharmacologic treatments in TBI (Narayan et al., 2002; Xiong et al., 2013; Skolnick et al., 2014; Wright et al., 2014).”
BackgroundBrody, D. L., Donald, C. M., Kessens, C. C., Yuede, C. M., Parsadanian, M., Spinner, M., Kim, E., Schwetye, K. E., Holtzman, D. M., & Bayly, P. V. (2007) · Journal of Neurotrauma · doi:10.1089/neu.2006.0011 · Cited by 197
“However, despite substantial research effort, effective therapeutics have not been developed, and further preclinical and clinical research tools are needed (Narayan et al., 2002).”
NAAG peptidase inhibitors and their potential for diagnosis and therapy
Zhou, J., Neale, J., Pomper, M., & Kozikowski, A. (2005) · Nature reviews. Drug discovery · doi:10.1038/nrd1903 · Cited by 209
Cytokines and innate inflammation in the pathogenesis of human traumatic brain injury.
Helmy, A., Simoni, M. D., Guilfoyle, M., Carpenter, K., & Hutchinson, P. (2011) · Progress in neurobiology · doi:10.1016/j.pneurobio.2011.09.003 · Cited by 208
Rockswold, S. B., Rockswold, G., Zaun, D., Zhang, X., Cerra, C., Bergman, T. A., & Liu, J.-N. (2010) · Journal of Neurosurgery · doi:10.3171/2009.7.jns09363 · Cited by 208
“Despite the tremendous negative impact on societies throughout the world and many multicenter therapeutic trials, no specific treatment for TBI is available.(47,66) A prospective, randomized clinical trial to compare the effect of hyperbaric to normobaric hyperoxia on cerebral metabolism, intracranial pressure, and ox…”
BackgroundInfluentialMaas, A. I. R., Menon, D. K., Lingsma, H. F., Pineda, J. A., Sandel, M. E., & Manley, G. T. (2011) · Journal of Neurotrauma · doi:10.1089/neu.2010.1599 · Cited by 203
Self-citationEffect of early nutrition on deaths due to severe traumatic brain injury.
Härtl, R., Gerber, L., Ni, Q.-H., & Ghajar, J. (2008) · Journal of Neurosurgery · doi:10.3171/jns/2008/109/7/0050 · Cited by 196
Self-citationDeWitt, D. S., & Prough, D. S. (2003) · Journal of Neurotrauma · doi:10.1089/089771503322385755 · Cited by 195
“Ideally, the same agents will demonstrate efficacy in multiple laboratories using different TBI models in two or more species before pro-ceeding to human trials (see McIntosh et al., Preclinical Testing , in Narayan et al., 2002).”
Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions
Jarrahi, A., Braun, M., Ahluwalia, M., Gupta, R. V., Wilson, M., Munie, S., Ahluwalia, P. K., Vender, J. R., Vale, F. Ĺ., Dhandapani, K. M., et al. (2020) · Biomedicines · doi:10.3390/biomedicines8100389 · Cited by 241
“Similarly, persistent elevated glutamate in cerebral tissue and CSF link with TBI severity in patients [12,13].”
BackgroundUnderstanding Secondary Injury
Borgens, R. B., & Liu‐Snyder, P. (2012) · The Quarterly Review of Biology · doi:10.1086/665457 · Cited by 203
Bellinger, D. C. (2011) · Environmental Health Perspectives · doi:10.1289/ehp.1104170 · Cited by 197
Kozai, T. D. Y., Marzullo, T., Hooi, F. M., Langhals, N. B., Majewska, A. K., Brown, E. B., & Kipke, D. R. (2010) · Journal of Neural Engineering · doi:10.1088/1741-2560/7/4/046011 · Cited by 184
“This vasogenic edema leads to increased brain tissue volume and intracranial pressure (Barzo et al 1997) often associated with their impact on tissue damage (Dixon et al 1991, McIntosh et al 1996) and clinical outcome (Narayan et al 2002).”
BackgroundReplication and reproducibility in spinal cord injury research
Steward, O., Popovich, P. G., Dietrich, W. D., & Kleitman, N. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2011.06.017 · Cited by 186
Self-citationThe added value of ordinal analysis in clinical trials: an example in traumatic brain injury
Roozenbeek, B., Lingsma, H. F., Perel, P., Edwards, P. J., Roberts, I., Murray, G. D., Maas, A. I. R., & Steyerberg, E. W. (2011) · Critical Care · doi:10.1186/cc10240 · Cited by 191
“Heterogeneity of the population and limitations of the conventional statistical analysis of TBI trials contribute to this lack of success [2,3].”
BackgroundSelf-citationAntihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH): Rationale and Design
Qureshi, A. I. (2007) · Neurocritical Care · doi:10.1385/ncc:6:1:56 · Cited by 131
Neuroprotective Strategies for Traumatic Brain Injury: Improving Clinical Translation
Kabadi, S. V., & Faden, A. I. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15011216 · Cited by 177
“Despite considerable success in elucidating secondary injury mechanisms, more than 30 phase III prospective trials of targeted drug therapies that showed promise in experimental models, have failed to generate favorable results under clinical settings [24–26].”
BackgroundHowe, J., Inness, E., Venturini, A., Williams, J., & Verrier, M. (2006) · Clinical Rehabilitation · doi:10.1177/0269215506072183 · Cited by 183
Recent progress of drug nanoformulations targeting to brain
Khan, A. R., Yang, X., Fu, M., & Zhai, G. (2018) · Journal of Controlled Release · doi:10.1016/j.jconrel.2018.10.004 · Cited by 216
Blood-based diagnostics of traumatic brain injuries
Mondello, S., Muller, U., Jeromin, A., Streeter, J., Hayes, R., & Wang, K. K. W. (2011) · Expert Review of Molecular Diagnostics · doi:10.1586/erm.10.104 · Cited by 181
Pharmacology of Traumatic Brain Injury: Where Is the “Golden Bullet”?
Beauchamp, K. M., Mutlak, H., Smith, W. R., Shohami, E., & Stahel, P. (2008) · Molecular Medicine · doi:10.2119/2008-00050.beauchamp · Cited by 178
Mussack, T., Biberthaler, P., Kanz, K., Wiedemann, E., Gippner‐Steppert, C., Mutschler, W., & Jochum, M. (2002) · Critical Care Medicine · doi:10.1097/00003246-200212000-00010 · Cited by 171
“In first-line therapy, the differentiation between patients who may benefit from neuroprotective strategies (such as mild hypothermia, mannitol, barbiturates, steroids, free radical scavengers, and diverse channel blockers or cerebral blood flow promotion with hypertension) (42) and those patients who persistently exc…”
BackgroundEffect of growth hormone replacement therapy on cognition after traumatic brain injury
High, W. M., Briones-Galang, M., Clark, J. A., Gilkison, C., Mossberg, K. A., Zgaljardic, D. J., Masel, B. E., & Urban, R. J. (2010) · Journal of Neurotrauma · doi:10.1089/neu.2009.1253 · Cited by 176
“Most strategies for intervention have focused on acute interventions with neuroprotective agents (Clifton, 2002, 2004; Empey et al.,2006; Narayan et al., 2002).”
Nichol, A., Higgins, A. M., Gabbe, B. J., Murray, L. J., Cooper, D. J., & Cameron, P. A. (2010) · Injury · doi:10.1016/j.injury.2010.11.047 · Cited by 193
Understanding Acquired Brain Injury: A Review
Goldman, L. V., Siddiqui, E. M., Khan, A., Jahan, S., Rehman, M. U., Mehan, S., Sharma, R. K., Budkin, S., Kumar, S. N., Sahu, A., et al. (2022) · Biomedicines · doi:10.3390/biomedicines10092167 · Cited by 205
“Post-traumatic stress disorder can occur even though there is no continuous recollection of head trauma [167].”
Background
Metadata
- Authors
- Narayan, R. K., Michel, M. E., Ansell, B., Baethmann, A., Biegon, A., Bracken, M. B., Bullock, M. R., Choi, S. C., Clifton, G. L., Contant, C. F., Coplin, W. M., Dietrich, W. D., Ghajar, J., Grady, S. M., Grossman, R. G., Hall, E. D., Heetderks, W., Hovda, D. A., Jallo, J., Katz, R. L., Knoller, N., Kochanek, P. M., Maas, A. I., Majde, J., Marion, D. W., Marmarou, A., Marshall, L. F., McIntosh, T. K., Miller, E., Mohberg, N., Muizelaar, J. P., Pitts, L. H., Quinn, P., Riesenfeld, G., Robertson, C. S., Strauss, K. I., Teasdale, G., Temkin, N., Tuma, R., Wade, C., Walker, M. D., Weinrich, M., Whyte, J., Wilberger, J., Young, A. B., & Yurkewicz, L.
- Affiliations
- Temple University Hospital (US)
- National Institute of Neurological Disorders and Stroke (US)
- National Institutes of Health (US)
- Ludwig-Maximilians-Universität München (DE)
- Lawrence Berkeley National Laboratory (US)
- Yale University (US)
- Virginia Commonwealth University (US)
- The University of Texas Health Science Center at Houston (US)
- Baylor College of Medicine (US)
- Wayne State University (US)
- University of Miami (US)
- Brain Trauma Foundation (US)
- Hospital of the University of Pennsylvania (US)
- Pfizer (United States) (US)
- University of California, Los Angeles (US)
- Temple University (US)
- United States Food and Drug Administration (US)
- Sheba Medical Center (IL)
- University of Pittsburgh (US)
- Academisch Ziekenhuis Rotterdam (NL)
- Office of Naval Research (US)
- University of California San Diego (US)
- University of California Davis Medical Center (US)
- University of California, San Francisco (US)
- Southern General Hospital (GB)
- University of Washington (US)
- Allegheny General Hospital (US)
- Albert B. Chandler Hospital (US)
- ORCID
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2002-05
- Volume
- 19
- Issue
- 5
- Pages
- 503-557
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- PMC
- PMC1462953
- OpenAlex
- W2045663952
- Cited by
- 913
- References
- 0
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 20 · 2023: 14 · 2022: 15 · 2021: 20 · 2020: 35 · 2019: 43 · 2018: 43 · 2017: 40 · 2016: 42 · 2015: 55 · 2014: 49 · 2013: 56 · 2012: 61
- FWCI
- 20.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurotrauma (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- Deep Blue (University of Michigan) (submittedVersion, public-domain)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- National Institutes of Health (7r01ns038654-04)
- National Institute of Neurological Disorders and Stroke (R01-NS038654)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
- Physical Sciences › Engineering › Biomedical Engineering › Automotive and Human Injury Biomechanics
- Keywords
- traumatic brain injury, clinical trial design, closed head injury, penetrating head injury, translational research, treatment failure, long-term disability
- MeSH terms
- Brain Injuries, Clinical Trials as Topic, Humans
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