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Clinical Trials in Traumatic Brain Injury: Past Experience and Current Developments
Open accessAbstract
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search of the years from 1980 to 2009 revealed 27 large phase III trials in TBI; we were aware of a further 6 unpublished trials.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.
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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 [36]
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Cites
Moderate and severe traumatic brain injury in adults
Maas, A. I., Stocchetti, N., & Bullock, R. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70164-9 · Cited by 2,123
Self-citationThe Incidence and Economic Burden of Injuries in the United States
Finkelstein, E. A., Corso, P. S., & Miller, T. R. (2006) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780195179484.001.0001 · Cited by 936
Clinical trials in head injury
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., et al. (2002) · Journal of Neurotrauma · doi:10.1089/089771502753754037 · Cited by 913
Self-citationPrevention of secondary ischemic insults after severe head injury
Robertson, C. S., Valadka, A. B., Hannay, H. J., Contant, C. F., Gopinath, S. P., Cormio, M., Uzura, M., & Grossman, R. G. (1999) · Critical Care Medicine · doi:10.1097/00003246-199910000-00002 · Cited by 748
Progressive hemorrhage after head trauma: predictors and consequences of the evolving injury
Oertel, M. F., Kelly, D. F., McArthur, D. A., Boscardin, W. J., Glenn, T. C., Lee, J. H., Gravori, T., Obukhov, D., McBride, D. Q., & Martin, N. A. (2002) · Journal of neurosurgery · doi:10.3171/jns.2002.96.1.0109 · Cited by 482
Xiao, G., Wei, J., Yan, W., Wang, W., & Lu, Z. (2008) · Critical Care · doi:10.1186/cc6887 · Cited by 463
Cooper, D. J., Myles, P. S., McDermott, F. T., Murray, L., Laidlaw, J. D., Cooper, G., Tremayne, A. B., Bernard, S., Ponsford, J. L., & For the HTS Study Investigators For the HTS Study Investigators (2004) · JAMA · doi:10.1001/jama.291.11.1350 · Cited by 461
Prognosis and Clinical Trial Design in Traumatic Brain Injury: The IMPACT Study
Maas, A., Marmarou, A., Murray, G., Teasdale, G., & Steyerberg, E. (2007) · Journal of Neurotrauma · doi:10.1089/neu.2006.0024 · Cited by 366
Self-citationA multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury
Marshall, L. F., Maas, A. I. R., Marshall, S. B., Bricolo, A., Fearnside, M. R., Iannotti, F., Klauber, M. R., Lagarrigue, J., Lobato, R., Persson, L., et al. (1998) · Journal of neurosurgery · doi:10.3171/jns.1998.89.4.0519 · Cited by 336
Self-citation
Research works printed but not linked: 2
- Maas, 1999, Why have recent trials of neuroprotective agents in head injury failed to show convincing efficacy?, Neurosurgery, 44, 1286
- Gaab, 1994, “Ultrahigh” dexamethasone in acute brain injury, Zentralbl Neurochir, 55, 135
Cited by
Sorted by citations
Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research
Maas, A. I. R., Menon, D. K., Adelson, P. D., Andelic, N., Bell, M. J., Belli, A., Bragge, P., Brazinova, A., Büki, A., Chesnut, R. M., et al. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30371-x · Cited by 2,609
Self-citationDecompressive Craniectomy in Diffuse Traumatic Brain Injury
Cooper, D. J., Rosenfeld, J. V., Murray, L., Arabi, Y. M., Davies, A. R., D’Urso, P., Kossmann, T., Ponsford, J. L., Seppelt, I., Reilly, P. L., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1102077 · Cited by 1,661
Traumatic Brain Injuries: Pathophysiology and Potential Therapeutic Targets
Ng, S. Y., & Lee, A. Y. W. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00528 · Cited by 906
“The L-type voltage-sensitive calcium channel antagonist nimodipine was also found to have beneficial effect for memory impairment in rats, though clinical trials were terminated because of its hypotensive effects and the lack of improvement in intracranial pressure observed in TBI survivors (Bailey et al., 1991; Veng…”
BackgroundMicroglia in the TBI brain: The good, the bad, and the dysregulated
Loane, D. J., & Kumar, A. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.08.018 · Cited by 846
“Historically, broad-spectrum anti-inflammatory therapies for TBI have translated poorly to the clinic for human head injury (Kumar and Loane, 2012; Maas et al., 2010), whichmay in part reflect loss of beneficialM2-like effects inmicroglia.”
BackgroundNeuroinflammation after traumatic brain injury: Opportunities for therapeutic intervention
Kumar, A., & Loane, D. J. (2012) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2012.06.008 · Cited by 710
“However, translation of promising experimental neuroprotective treatments to human injury have been very disappointing, with none of the pharmacological treatments resulting in any consistent improvements in outcome in the clinic (Maas et al., 2010).”
Blennow, K., Brody, D. L., Kochanek, P. M., Levin, H. S., McKee, A. C., Ribbers, G. M., Yaffe, K. S., & Zetterberg, H. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.84 · Cited by 693
Loane, D. J., & Faden, A. I. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.09.005 · Cited by 574
“Although preclinical studies have suggested many promising pharmacological agents, more than 30 phase III prospective clinical trials have failed to show significance for their primary endpoint [8–10].”
BackgroundThe Flaws and Human Harms of Animal Experimentation
AKHTAR, A. (2015) · Cambridge Quarterly of Healthcare Ethics · doi:10.1017/s0963180115000079 · Cited by 527
Global neurotrauma research challenges and opportunities
Rubiano, A., Carney, N., Chesnut, R., & Puyana, J. (2015) · Nature · doi:10.1038/nature16035 · Cited by 479
Yue, J. K., Vassar, M. J., Lingsma, H. F., Cooper, S. R., Okonkwo, D. O., Valadka, A. B., Gordon, W. A., Maas, A. I. R., Mukherjee, P., Yuh, E. L., et al. (2013) · Journal of Neurotrauma · doi:10.1089/neu.2013.2970 · Cited by 371
“The heterogeneity of TBI combined with the lack of relevant and validated outcome measures have been central to the discouraging results from neuroprotective and therapeutic strategy trials over the last four decades.(8) Current approaches to the characterization of disease severity and outcome have not changed in mor…”
Self-citationTraumatic Axonal Injury: Mechanisms and Translational Opportunities
Hill, C. S., Coleman, M. P., & Menon, D. K. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.03.002 · Cited by 327
“Concluding Remarks: Mechanistic Understanding May Translate to Therapies Despite increasing interest in and research into TAI, there has so far been a notable lack of translation into efficacious patient therapies [70].”
BackgroundJi, J., Kline, A. E., Amoscato, A. A., Samhan-Arias, A. K., Sparvero, L. J., Tyurin, V. A., Tyurina, Y. Y., Fink, B., Manole, M. D., Puccio, A. M., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.3195 · Cited by 314
Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial
Nichol, A., French, C., Little, L., Haddad, S. H., Presneill, J., Arabi, Y. M., Bailey, M., Cooper, D. J., Duranteau, J., Huet, O., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(15)00386-4 · Cited by 275
Imaging for the diagnosis and management of traumatic brain injury
Kim, J. J., & Gean, A. D. (2011) · Neurotherapeutics · doi:10.1007/s13311-010-0003-3 · Cited by 249
“Numerous neuroprotective strategies, including the use of agents to antagonize excessive excitotoxic glutamate activity, block voltage-gated calcium channels and intracellular calcium influx, reduce mitochondrial dysfunction, and limit free radical damage, have been evaluated in both experimental animal models and cli…”
Photobiomodulation and the brain: a new paradigm
Hennessy, M., & Hamblin, M. R. (2016) · Journal of Optics · doi:10.1088/2040-8986/19/1/013003 · Cited by 243
Diagnosing Level of Consciousness: The Limits of the Glasgow Coma Scale Total Score
Bodien, Y. G., Barra, A., Temkin, N. R., Barber, J. K., Foreman, B. P., Vassar, M. J., Robertson, C. S., Taylor, S. R., Markowitz, A. J., Manley, G. T., et al. (2021) · Journal of Neurotrauma · doi:10.1089/neu.2021.0199 · Cited by 233
Self-citationAngiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders
Saavedra, J. M. (2012) · Clinical Science · doi:10.1042/cs20120078 · Cited by 221
Maas, 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
“In TBI, these trials have been conducted on a range of neuroprotective agents and surgical and medical approaches (Maas et al., 2010a).”
InfluentialSelf-citationKalra, S., Malik, R., Singh, G., Bhatia, S., Al‐Harrasi, A., Mohan, S., Albratty, M., Albarrati, A., & Tambuwala, M. M. (2022) · Inflammopharmacology · doi:10.1007/s10787-022-01017-8 · Cited by 211
The 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
“Since the 1980s, at least 33 randomized controlled phase III trials have been performed to investigate the effectiveness of new therapeutic interventions in TBI, but none has convincingly demonstrated benefit in the overall population [1].”
BackgroundSelf-citationMaas, A. I. R., Murray, G. D., Roozenbeek, B., Lingsma, H. F., Butcher, I., McHugh, G. S., Weir, J., Lü, J., & Steyerberg, E. W. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70234-5 · Cited by 172
Self-citationUnderstanding 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
“Nimodipine, triamcinolone, polyethylene glycol-conjugated superoxide dismutase, and mild hypothermia have all shown positive results in phase II clinical trials [162].”
BackgroundNeuroprotective 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
“aspx) [10,24].”
BackgroundReturn to work after traumatic brain injury: Systematic review
Saltychev, M., Eskola, M., Tenovuo, O. S., & Laimi, K. (2013) · Brain Injury · doi:10.3109/02699052.2013.831131 · Cited by 169
Melatonin attenuates traumatic brain injury‐induced inflammation: a possible role for mitophagy
Lin, C., Chao, H., Li, Z., Xu, X., Liu, Y., Hou, L.-J., Liu, N., & Ji, J. (2016) · Journal of Pineal Research · doi:10.1111/jpi.12337 · Cited by 170
“Interestingly, no neuroprotective agents have demonstrated great improvement in outcomes for these patients as determined by randomized controlled trials [1, 3].”
BackgroundTucker, L. B., Fu, A. H., & McCabe, J. T. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2015.3977 · Cited by 170
Maas, A. I. R., Steyerberg, E. W., Marmarou, A., McHugh, G. S., Lingsma, H. F., Butcher, I., Lu, J., Weir, J., Roozenbeek, B., & Murray, G. D. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2009.10.020 · Cited by 157
Self-citationLei, J., Gao, G., Feng, J., Jin, Y., Wang, C., Mao, Q., & Jiang, J. (2015) · Critical Care · doi:10.1186/s13054-015-1081-8 · Cited by 147
“[24, 25].”
Pathophysiological Responses and Roles of Astrocytes in Traumatic Brain Injury
Michinaga, S., & Kōyama, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126418 · Cited by 148
The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease
Kokiko-Cochran, O. N., & Godbout, J. P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00672 · Cited by 128
Traumatic Brain Injury, Neuroinflammation, and Post-Traumatic Headaches
Mayer, C. L., Huber, B., & Peskind, E. (2013) · Headache · doi:10.1111/head.12173 · Cited by 119
Bragge, P., Synnot, A., Maas, A. I. R., Menon, D. K., Cooper, D. J., Rosenfeld, J. V., & Gruen, R. L. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2015.4233 · Cited by 126
“Notwithstanding this, lack of successful translation from laboratory-based research to effective TBI treatments also was noted in our previous reviews.(7,24,25) It appears from our graphical analysis that lack of positive RCT findings is not a function of trial characteristics including sample size and risk of bias.”
BackgroundMethodSelf-citationMechanisms and Potential Therapeutic Applications of Microglial Activation after Brain Injury
Kim, J. Y., Kim, N., & Yenari, M. A. (2014) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12360 · Cited by 125
“While many of these drugs have produced promising preclinical results, there has been little headway in pharmacological treatments for acute injury at the clinical level [183,184].”
BackgroundLogan, S., Arzua, T., Canfield, S. G., Seminary, E. R., Sison, S. L., Ebert, A. D., & Bai, X. (2019) · Comprehensive physiology · doi:10.1002/cphy.c180025 · Cited by 143
“Many prospective drugs for stroke, traumatic brain injury (TBI), and AD were found to be effective in animal experiments; however, these same drugs failed in clinical trials (4,276,401,439,457).”
Campbell, M., Hanrahan, F., Gobbo, O. L., Kelly, M. E., Kiang, A., Humphries, M. M., Nguyen, A. T. H., Ozaki, E., Keaney, J., Blau, C. W., et al. (2012) · Nature Communications · doi:10.1038/ncomms1852 · Cited by 113
NADPH oxidases in traumatic brain injury – Promising therapeutic targets?
Ma, M. W., Wang, J., Dhandapani, K. M., Wang, R., & Brann, D. W. (2018) · Redox Biology · doi:10.1016/j.redox.2018.03.005 · Cited by 116
Cooper, D. J., Rosenfeld, J. V., Murray, L., Arabi, Y. M., Davies, A. R., Ponsford, J. L., Seppelt, I., Reilly, P. L., Wiegers, E., Wolfe, R. S., et al. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2019.6869 · Cited by 112
Prognostic Value of Major Extracranial Injury in Traumatic Brain Injury
van Leeuwen, N., Lingsma, H. F., Perel, P., Lecky, F. E., Roozenbeek, B., Lü, J., Shakur‐Still, H., Weir, J., Steyerberg, E. W., & Maas, A. I. R. (2011) · Neurosurgery · doi:10.1227/neu.0b013e318235d640 · Cited by 109
Self-citationProgesterone in the clinical treatment of acute traumatic brain injury
Stein, D. G., & Wright, D. W. (2010) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2010.489549 · Cited by 108
“In Europe, close to 7 million disabled people are living with the consequences of TBI [1], and in China over 3 million people a year are reported to suffer a brain injury [2-6].”
BackgroundChen, J., HU, J. L., Liu, H., Xiong, Y., Zou, Y., Huang, W., Shao, M., Wu, J., Yu, L., Wang, X., et al. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2017.5271 · Cited by 106
Kota, D. J., Prabhakara, K. S., Furman, N. E. T., Bhattarai, D., Chen, Q., DiCarlo, B., Smith, P., Triolo, F., Wenzel, P. L., Cox, C. S., et al. (2017) · Stem Cells · doi:10.1002/stem.2603 · Cited by 105
Neuroprotection for traumatic brain injury
Loane, D. J., Stoica, B. A., & Faden, A. I. (2015) · Handbook of clinical neurology · doi:10.1016/b978-0-444-52892-6.00022-2 · Cited by 104
“Although preclinical studies have suggested many promising pharmacologic agents, more than 30 phase III prospective clinical trials have failed to show significance for their primary end point (Narayan et al., 2002; Schouten, 2007; Maas et al., 2010).”
BackgroundNielson, J. L., Cooper, S. R., Yue, J. K., Sorani, M. D., Inoue, T., Yuh, E. L., Mukherjee, P., Petrossian, T. C., Paquette, J., Lum, P. Y., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0169490 · Cited by 100
Self-citationHakiminia, B., Alikiaii, B., Khorvash, F., & Mousavi, S. (2022) · Fundamental and Clinical Pharmacology · doi:10.1111/fcp.12767 · Cited by 106
“1 | Combination of antioxidant agents for TBI treatment Generally, the favorable results obtained from preclinical studies of TBI assessing effects of antioxidant agents have not fully been confirmed in clinical trials [274, 275].”
BackgroundHaus, D. L., López-Velázquez, L., Gold, E. M., Cunningham, K. M., Perez, H. D., Anderson, A. J., & Cummings, B. J. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.04.008 · Cited by 99
“Considering that many pharmacologic interventions for TBI have been shown to be ineffective in clinical trials (Xiong et al., 2009; Maas et al., 2010; Lu et al., 2012), new treatment options must be explored.”
BackgroundNeurotransmitter changes after traumatic brain injury: an update for new treatment strategies
McGuire, J. L., Ngwenya, L. B., & McCullumsmith, R. E. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0239-6 · Cited by 101
Pleasant, J. M., Carlson, S. W., Mao, H., Scheff, S. W., Yang, K. H., & Saatman, K. E. (2011) · Journal of Neurotrauma · doi:10.1089/neu.2010.1499 · Cited by 94
“Although numerous clinical trials have been conducted for moderate-to-severe TBI, no therapeutic intervention has proven effective in improving functional outcome (Maas et al., 2010; Narayan et al., 2002).”
Investigational agents for treatment of traumatic brain injury
Xiong, Y., Zhang, Y.-L., Mahmood, A., & Chopp, M. (2015) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2015.1021919 · Cited by 82
“Over the past 40 years, > 100 RCTs in TBI were conducted [11,23,34-41].”
BackgroundAntagonism of purinergic signalling improves recovery from traumatic brain injury.
Choo, A., Miller, W., Chen, Y., Nibley, P. D., Patel, T. P., Goletiani, C., Morrison, B., Kutzing, M. K., Firestein, B., Sul, J., et al. (2013) · Brain : a journal of neurology · doi:10.1093/brain/aws286 · Cited by 92
“Traumatic brain injury is a complex and evolving disease, and some treatments have progressed recently to human clinical trials (Maas et al., 2010).”
BackgroundKuriakose, M., Younger, D., Ravula, A. R., Alay, E., Rao, K. V. R., & Chandra, N. (2019) · Scientific Reports · doi:10.1038/s41598-019-44147-w · Cited by 91
Pre-Clinical Testing of Therapies for Traumatic Brain Injury
DeWitt, D. S., Hawkins, B. E., Dixon, C. E., Kochanek, P. M., Armstead, W. M., Bass, C. R., Bramlett, H. M., Büki, A., Dietrich, W. D., Ferguson, A. R., et al. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2018.5778 · Cited by 87
“14,69,70 Maas and associates 71 observed that most of the trials that reported beneficial effects of the therapy tested were single-center RCTs.”
Nairuz, T., Sangwoo-Cho, & Lee, J.-H. (2024) · Cells · doi:10.3390/cells13110966 · Cited by 84
“Given the considerable challenges encountered in developing pharmaceutical interventions for conditions like stroke [169] and TBI [170], where progress has been largely elusive despite substantial investments, there is a compelling case for a broader exploration of PBM’s potential.”
BackgroundTraumatic Brain Injury – Modeling Neuropsychiatric Symptoms in Rodents
Malkesman, O., Tucker, L. B., Ozl, J., & McCabe, J. T. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00157 · Cited by 85
Randomized controlled trials in adult traumatic brain injury
Lü, J., Gary, K. W., Neimeier, J. P., Ward, J., & Lapane, K. L. (2012) · Brain Injury · doi:10.3109/02699052.2012.722257 · Cited by 80
“The search results were then compared against the review articles related to trials targeting the acute phase [6] and post-acute phase of TBI [7, 8].”
BackgroundResultInfluentialErdman, J. W., Oria, M. P., & Pillsbury, L. (2011) · Cited by 79
Is aggressive treatment of traumatic brain injury cost-effective?
Whitmore, R. G., Thawani, J. P., Grady, M. S., Levine, J. M., Sanborn, M. R., & Stein, S. C. (2012) · Journal of neurosurgery · doi:10.3171/2012.1.jns11962 · Cited by 77
Corrigan, F., Pham, C. L. L., Vink, R., Blumbergs, P. C., Masters, C. L., van den Heuvel, C., & Cappai, R. (2011) · Brain Research · doi:10.1016/j.brainres.2010.12.077 · Cited by 75
The NLRP3 inflammasome: a potential therapeutic target for traumatic brain injury
Ishrat, T., Ismael, S., Ahmed, H. A., Adris, T., Parveen, K., & Thakor, P. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.286951 · Cited by 74
“More than thirty prospective clinical trials for treating TBI have not shown significant promise, as these trials focused on single mechanisms of secondary injury while the mechanisms involved in TBI are clearly multifactorial in nature (Maas et al., 2010).”
BackgroundStanley, R., Bonsu, B. K., Zhao, W., Ehrlich, P., Rogers, A., & Xiang, H. (2012) · Pediatrics · doi:10.1542/peds.2011-2074 · Cited by 67
Kuriakose, M., Rao, K. V. R., Younger, D., & Chandra, N. (2018) · Scientific Reports · doi:10.1038/s41598-018-26813-7 · Cited by 73
Microglia Receptors in Animal Models of Traumatic Brain Injury
Younger, D., Murugan, M., Rao, K. V. R., Wu, L., & Chandra, N. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1428-7 · Cited by 69
Novel Therapeutic Strategies for Traumatic Brain Injury: Acute Antioxidant Reinforcement
Fernández-Gajardo, R., Matamala, J. M., Carrasco, R. A., Gutiérrez, R., Melo, R., & Rodrigo, R. (2014) · CNS Drugs · doi:10.1007/s40263-013-0138-y · Cited by 69
“have failed to display significance for their primary outcome [258–260].”
Backgroundvan Erp, I. A. M., Michailidou, I., van Essen, T. A., van der Jagt, M., Moojen, W. A., Peul, W. C., Baas, F., & Fluiter, K. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01306-8 · Cited by 71
“Despite the vast amount of research performed to improve our understanding of the pathophysiology in TBI, the field has repeatedly experienced collective failures to translate research from animals to successful therapeutic application in humans [11, 12].”
BackgroundGao, Y., Li, J., Wu, L., Zhou, C., Wang, Q., Li, X., Zhou, M., & Wang, H. (2016) · Journal of Surgical Research · doi:10.1016/j.jss.2016.07.014 · Cited by 66
Targeting mTOR as a novel therapeutic strategy for traumatic CNS injuries
Don, A. S. A., Tsang, C. K., Kazdoba, T. M., D’Arcangelo, G., Young, W., & Zheng, X. (2012) · Drug Discovery Today · doi:10.1016/j.drudis.2012.04.010 · Cited by 68
Kontos, A. P., Collins, M. W., Holland, C. L., Reeves, V. L., Edelman, K. L., Benso, S., Schneider, W., & Okonkwo, D. O. (2018) · Military Medicine · doi:10.1093/milmed/usx172 · Cited by 66
Pleiotropic neuroprotective and metabolic effects of Actovegin's mode of action
Machicao, F. E., Muresanu, D. F., Hundsberger, H., Pflüger, M., & Guekht, A. B. (2012) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2012.07.069 · Cited by 64
“However, what is clear from clinical trials in neuroprotection is that the suppression subtractive strategywith chemical drugs does notwork [2,3].”
Past, Present, and Future of Traumatic Brain Injury Research
Hawryluk, G. W. J., & Bullock, M. R. (2016) · Neurosurgery Clinics of North America · doi:10.1016/j.nec.2016.05.002 · Cited by 69
“Paralleling this basic science advancement is recognition of the methodologic shortcomings of the approximately 35 phase III TBI trials undertaken to date, which likely contributed to their failure.(3) There is thus great optimism that victims of TBI may soon benefit from novel and efficacious therapeutics that have b…”
BackgroundResultInfluentialFolweiler, K. A., Sandsmark, D. K., Diaz-Arrastia, R. R., Cohen, A. S., & Masino, A. J. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2019.6705 · Cited by 63
Traumatic brain injury: Changing concepts and approaches
Maas, A. I. R. (2016) · Chinese Journal of Traumatology · doi:10.1016/j.cjtee.2016.01.001 · Cited by 62
Self-citationThe Influence of Dietary Factors in Central Nervous System Plasticity and Injury Recovery
Gómez‐Pinilla, F., & Gomez, A. G. (2011) · PM&R · doi:10.1016/j.pmrj.2011.03.001 · Cited by 62
Towards a roadmap in brain protection and recovery
Muresanu, D. F., Buzoianu, A. D., Florian, I. Ş., & von Wild, T. (2012) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2012.01605.x · Cited by 58
“[4], the only drug that showed significant results was progesterone, which is also a non-suppressive, multimodal agent with pleiotropic neuroprotective effect [32].”
BackgroundTRIVEDI, R. B., & Humphreys, K. N. (2015) · Contemporary Clinical Trials · doi:10.1016/j.cct.2015.07.009 · Cited by 56
“Among neurological disorders, the IMPACT (International Mission on Prognosis and Clinical Trial Design in TBI) multidisciplinary group was formed with the mission to develop better approaches to phase III TBI trials [9,28].”
MethodDynamic neural and glial responses of a head-specific model for traumatic brain injury in Drosophila
Saikumar, J., Byrns, C. N., Hemphill, M. A., Meaney, D. F., & Bonini, N. M. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2003909117 · Cited by 53
Muresanu, D. F., Florian, I. Ş., Hömberg, V., Matula, C., von Steinbüchel, N., Vos, P. E., Wild, K. V., Bîrle, C., Mureșanu, I. A., Slăvoacă, D., et al. (2020) · Neurological Sciences · doi:10.1007/s10072-019-04181-y · Cited by 56
“According to an in-depth review performed in 2010, the majority of randomized controlled trials (RCTs) used a single outcome measure model with arbitrary dichotomization of continuous variables and had other essential flaws, notably not adjusting the research design to the complexity of TBI [4].”
BackgroundBrett, B. L., Kramer, M. D., Whyte, J., McCrea, M., Stein, M. B., Giacino, J. T., Sherer, M., Markowitz, A. J., Manley, G. T., Nelson, L. D., et al. (2021) · JAMA Network Open · doi:10.1001/jamanetworkopen.2021.3467 · Cited by 55
Self-citationStover, J. F., Belli, A., Boret, H., Bulters, D., Sahuquillo, J., Schmutzhard, E., Zavala, E., Ungerstedt, U., Schinzel, R., Tegtmeier, F., et al. (2014) · Journal of Neurotrauma · doi:10.1089/neu.2014.3344 · Cited by 53
Role of fibrinogen in cerebrovascular dysfunction after traumatic brain injury
Muradashvili, N., & Lominadze, D. G. (2013) · Brain Injury · doi:10.3109/02699052.2013.823562 · Cited by 54
“Traumatic brain injury (TBI) is the leading cause of death and disability, for which no effective treatment exists other than supportive care [1].”
BackgroundYuan, J., Zhang, J., Cao, J., Wang, G., & Bai, H. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00749-6 · Cited by 54
Nimer, F. A., Lindblom, R. P. F., Ström, M., Guerreiro‐Cacais, A. O., Parsa, R., Aeinehband, S., Mathiesen, T. I., Lidman, O., & Piehl, F. (2012) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2012.10.002 · Cited by 53
“Genetic variability may influence pathophysiological processes triggered by TBI, in turn of relevance for outcome and possibly also response to treatment (Dardiotis et al., 2010; Maas et al., 2010; McAllister, 2010; Zhou et al., 2008).”
InfluentialImatinib treatment reduces brain injury in a murine model of traumatic brain injury
Su, E. J., Fredriksson, L., Kanzawa, M., Moore, S. J., Folestad, E. B., Stevenson, T. K., Nilsson, I., Sashindranath, M., Schielke, G. P., Warnock, M., et al. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00385 · Cited by 52
“However, despite numerous studies in animal models of TBI and clinical trials of various therapeutic strategies, no effective therapy for TBI patients has emerged (Grumme et al., 1995; Marmarou et al., 1999; Bramlett and Dietrich, 2004; Yurkewicz et al., 2005; Maas et al., 2006, 2010).”
BackgroundBregy, A., Nixon, R. A., Lotocki, G., Alonso, O. F., Atkins, C. M., Tsoulfas, P., Bramlett, H. M., & Dietrich, W. D. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.12.008 · Cited by 53
“Although a significant amount of information is now known regarding the pathophysiology of brain injury (Bigler andMaxwell, 2011; Bramlett andDietrich, 2004), the successful translation to the clinic of therapeutic interventions shown to be promising in animal models has yet to be achieved (Maas et al., 2010).”
Kumar, R. G., Rubin, J. E., Berger, R. P., Kochanek, P. M., & Wagner, A. K. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.12.008 · Cited by 52
“Clinical trials have not been successful to date in identifying any definitive neuroprotective treatment (Maas et al. , 2010).”
Cellular microparticles and pathophysiology of traumatic brain injury
Zhao, Z., Zhou, Y., Tian, Y., Li, M., Dong, J., & Zhang, J. (2017) · Protein & Cell · doi:10.1007/s13238-017-0414-6 · Cited by 54
“Cellular microparticles produced by injured tissues have been increasingly recognized as a key mediator for the interplay, promoting a transition from primary injury to secondary injury (Maas et al., 2010; Stoica and Faden, 2010).”
BackgroundErythropoietin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy
Bramlett, H. M., Dietrich, W. D., Dixon, C. E., Shear, D. A., Schmid, K. E., Mondello, S., Wang, K., Hayes, R. L., Povlishock, J. T., Tortella, F. C., et al. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2015.4116 · Cited by 51
“5 There are various proposed reasons for this failure, including the complexity and heterogeneous nature of clinical TBI, as well as other limitations regarding adequate pre-clinical data to support the translation of therapies into the clinic.”
Raj, R., Mikkonen, E. D., Siironen, J. O., Hernesniemi, J. A., Lappalainen, J., & Skrifvars, M. B. (2015) · Journal of neurosurgery · doi:10.3171/2015.4.jns141746 · Cited by 51
Neuroprotection Trials in Traumatic Brain Injury
Chakraborty, S., Skolnick, B. E., & Narayan, R. K. (2016) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-016-0625-x · Cited by 50
Saraiva, A. L. L., Ferreira, A. P. O., Silva, L. F. A., Hoffmann, M. S., Dutra, F. D., Furian, A. F., Oliveira, M. S., Fighera, M. R., & Royes, L. F. F. (2012) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2011.10.010 · Cited by 49
Hu, B., Liu, X., Qiang, R., Jiang, Z., Xu, L., Wang, G., Li, X., & Peng, B. (2014) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2014.07.009 · Cited by 48
Branched Chain Amino Acids (BCAAs) and Traumatic Brain Injury: A Systematic Review
Sharma, B., Lawrence, D. W., & Hutchison, M. G. (2017) · Journal of Head Trauma Rehabilitation · doi:10.1097/htr.0000000000000280 · Cited by 48
Bodien, Y. G., McCrea, M., DIKMEN, S. S., Temkin, N. R., Boase, K., Machamer, J., Taylor, S. R., Sherer, M., Levin, H. S., Kramer, J. H., et al. (2018) · Journal of Head Trauma Rehabilitation · doi:10.1097/htr.0000000000000367 · Cited by 47
Self-citationRønning, P. A., Helseth, E., Skaga, N.-O., Stavem, K., & Langmoen, I. A. (2019) · Journal of neurosurgery · doi:10.3171/2018.7.jns18270 · Cited by 49
Therapeutic inducers of the HSP 70/ HSP 110 protect mice against traumatic brain injury
Eroglu, B., Kimbler, D. E., Pang, J., Choi, J., Moskophidis, D., Yanasak, N. E., Dhandapani, K. M., & Mivechi, N. F. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12781 · Cited by 48
Lagraoui, M., Sukumar, G., Latoche, J. R., Maynard, S. K., Dalgard, C. L., & Schaefer, B. C. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.12.005 · Cited by 47
“Given the uniform lack of success of clinical trials of TBI therapeutics to date (Maas et al., 2012, 2010), many in the TBI field now argue that multifactorial therapies are required, either in the form of multiple drugs targeting distinct aspects of the pathological response, or single drugs with…”
BackgroundMokhtari, M., Nayeb‐Aghaei, H., Kouchek, M., Miri, M., Goharani, R., Amoozandeh, A., Salamat, S. A., & Sistanizad, M. (2018) · Journal of clinical pharmacology · doi:10.1002/jcph.980 · Cited by 47
Validation of a prognostic score for early mortality in severe head injury cases
Gómez, P. A., de la Cruz, J., Lora, D., Roldan, L. J., Rodríguez-Boto, G., Sarabia, R., Sahuquillo, J., Lastra, R., Morera, J., Lazo-Fernández, E., et al. (2014) · Journal of neurosurgery · doi:10.3171/2014.7.jns131874 · Cited by 45
New considerations in the design of clinical trials for traumatic brain injury
Roozenbeek, B., Lingsma, H. F., & Maas, A. I. R. (2012) · Clinical Investigation · doi:10.4155/cli.11.179 · Cited by 44
Self-citationBudinich, C. S., Tucker, L. B., Lowe, D., Rosenberger, J. G., & McCabe, J. T. (2013) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.04.001 · Cited by 44
Operation Brain Trauma Therapy: 2016 Update
Kochanek, P. M., Bramlett, H. M., Dixon, C. E., Dietrich, W. D., Mondello, S., Wang, K., Hayes, R. L., Lafrenaye, A. D., Povlishock, J. T., Tortella, F. C., et al. (2018) · Military Medicine · doi:10.1093/milmed/usx184 · Cited by 44
Kaloostian, P., Robertson, C., Gopinath, S., Stippler, M., King, C. C., Qualls, C., Yonas, H., & Nemoto, E. (2012) · Journal of Neurotrauma · doi:10.1089/neu.2011.2147 · Cited by 44
“Second, it is also important for injury stratification for inclusion in randomized clinical trials (RCTs; Maas et al., 2007,2010).”
Metadata
- Authors
- Maas, A. I. R., Roozenbeek, B., & Manley, G. T.
- Affiliations
- Antwerp University Hospital (BE)
- Erasmus MC (NL)
- University of California, San Francisco (US)
- Corresponding author
- Maas, Andrew I.R.
- Venue
- Neurotherapeutics
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 7
- Issue
- 1
- Pages
- 115-126
- ISSN
- 1878-7479 (ISSN-L)
- PMC
- PMC5084118
- OpenAlex
- W2112462557
- Cited by
- 291
- References
- 44
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 12 · 2023: 13 · 2022: 21 · 2021: 10 · 2020: 17 · 2019: 20 · 2018: 26 · 2017: 19 · 2016: 24 · 2015: 24 · 2014: 20 · 2013: 16 · 2012: 28
- FWCI
- 2.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurotherapeutics (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- 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 trials, neuroprotective agents, decompressive craniectomy, therapeutic hypothermia, clinical trial registries, clinical trial design, data element standardization, individual patient data meta-analysis
- MeSH terms
- Brain Injuries, Clinical Trials as Topic, Humans
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