Safety and efficacy of C1-inhibitor in traumatic brain injury (CIAO@TBI): study protocol for a randomized, placebo-controlled, multi-center trial

Inge A M van Erp, Thomas A van Essen, Kees Fluiter, Erik van Zwet, Peter van Vliet, Frank Baas, Iain Haitsma, Dagmar Verbaan, Bert Coert, Godard C W de Ruiter, Wouter A Moojen, Mathieu van der Jagt, Wilco C Peul, Inge A M van Erp, Thomas A van Essen, Kees Fluiter, Erik van Zwet, Peter van Vliet, Frank Baas, Iain Haitsma, Dagmar Verbaan, Bert Coert, Godard C W de Ruiter, Wouter A Moojen, Mathieu van der Jagt, Wilco C Peul

Abstract

Background: Traumatic brain injury (TBI) is a major cause of death and disability across all ages. After the primary impact, the pathophysiologic process of secondary brain injury consists of a neuroinflammation response that critically leads to irreversible brain damage in the first days after the trauma. A key catalyst in this inflammatory process is the complement system. Inhibiting the complement system could therefore be a therapeutic target in TBI.

Objective: To study the safety and efficacy of C1-inhibitor (C1-INH) compared to placebo in patients with TBI. By temporarily blocking the complement system, we hypothesize a decrease in the posttraumatic neuroinflammatory response resulting in a less unfavorable clinical outcome for TBI patients.

Methods: CIAO@TBI is a multicenter, randomized, blinded, phase II placebo-controlled trial. Adult TBI patients with GCS < 13 requiring intracranial pressure (ICP) monitoring will be randomized, using block randomization, within 12 h after trauma to one dose 6000 IU C1-INH or placebo. A total of 106 patients will be included, and follow-up will occur up to 12 months. The primary endpoints are (1) Therapy Intensity Level (TIL) Scale, (2) Glasgow Outcome Scale-Extended (GOSE) at 6 months, and (3) complication rate during hospitalization. Outcomes will be determined by a trial nurse blinded for the treatment allocation. Analyses will be conducted in an intention-to-treat analysis.

Discussion: We expect that C1-INH administration will be safe and potentially effective to improve clinical outcomes by reducing neuroinflammation in TBI patients.

Trial registration: ClinicalTrials.gov NCT04489160. Registered on 27 July 2020. EudraCT 2020-000140-58.

Keywords: C1-inhibitor; Neuroinflammation; Randomized controlled trials; Traumatic brain injury.

Conflict of interest statement

WP reports to be part of the management team of the CENTER-TBI study (NCT02210221) and to be the principal investigator of the Net-Qure (NL5761), RESET-ASDH, and SPARTA trials. All other authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Contact, complement, coagulation, and fibrinolytic systems and targets of C1-INH. Abbreviations: MAC, membrane attack complex; HMWK, high-molecular-weight kininogen; C1-INH, C1-inhibitor; t-PA, tissue plasminogen activator; MASPs, mannose-associated serine protease. Explanation: C1-INH is directed at all three pathways of the complement system, but has also an effect on the contact, fibrinolytic, and coagulation system
Fig. 2
Fig. 2
CIAO@TBI study design flowchart. Abbreviations: TBI, traumatic brain injury; GCS, Glasgow Coma Scale; HAE, hereditary angio-edema; CSF, cerebrospinal fluid; TIL, therapy intensity level; GOSE, Glasgow Outcome Scale Extended; QoLiBri, Quality of Life after Brain Injury Scale; iPCQ, IMTA Productivity Cost Questionnaire; iMCQ,: IMTA Medical Consumption Questionnaire; SF-36, Short-Form 36; EQ-5D-5L, 5 Level EuroQoL 5-Dimensional Questionnaire
Fig. 3
Fig. 3
SPIRIT diagram of the recommended content for the schedule of enrollment, interventions, and assessments. Abbreviations: C1-INH, complement 1-inhibitor; TIL, therapy intensity level; (S)AEs, (serious) adverse events; ICP, intracranial pressure; CT, computed tomography; ICU, intensive care unit; LOS, length of stay; GOSE, Glasgow Outcome Scale Extended; QoLiBri, Quality of Life after Brain Injury Scale; iPCQ, iMTA Productivity Cost Questionnaire; iMCQ, iMTA Medical Cost Questionnaire; SF-36, Short-Form 36; EQ-5D-5L, 5 Level EuroQoL 5-Dimensional Questionnaire

References

    1. Maas AIR, Menon DK, Adelson PD, Andelic N, Bell MJ, Belli A, Bragge P, Brazinova A, Büki A, Chesnut RM, Citerio G, Coburn M, Cooper DJ, Crowder AT, Czeiter E, Czosnyka M, Diaz-Arrastia R, Dreier JP, Duhaime AC, Ercole A, van Essen TA, Feigin VL, Gao G, Giacino J, Gonzalez-Lara LE, Gruen RL, Gupta D, Hartings JA, Hill S, Jiang JY, Ketharanathan N, Kompanje EJO, Lanyon L, Laureys S, Lecky F, Levin H, Lingsma HF, Maegele M, Majdan M, Manley G, Marsteller J, Mascia L, McFadyen C, Mondello S, Newcombe V, Palotie A, Parizel PM, Peul W, Piercy J, Polinder S, Puybasset L, Rasmussen TE, Rossaint R, Smielewski P, Söderberg J, Stanworth SJ, Stein MB, von Steinbüchel N, Stewart W, Steyerberg EW, Stocchetti N, Synnot A, te Ao B, Tenovuo O, Theadom A, Tibboel D, Videtta W, Wang KKW, Williams WH, Wilson L, Yaffe K, Adams H, Agnoletti V, Allanson J, Amrein K, Andaluz N, Anke A, Antoni A, van As AB, Audibert G, Azaševac A, Azouvi P, Azzolini ML, Baciu C, Badenes R, Barlow KM, Bartels R, Bauerfeind U, Beauchamp M, Beer D, Beer R, Belda FJ, Bellander BM, Bellier R, Benali H, Benard T, Beqiri V, Beretta L, Bernard F, Bertolini G, Bilotta F, Blaabjerg M, den Boogert H, Boutis K, Bouzat P, Brooks B, Brorsson C, Bullinger M, Burns E, Calappi E, Cameron P, Carise E, Castaño-León AM, Causin F, Chevallard G, Chieregato A, Christie B, Cnossen M, Coles J, Collett J, Della Corte F, Craig W, Csato G, Csomos A, Curry N, Dahyot-Fizelier C, Dawes H, DeMatteo C, Depreitere B, Dewey D, van Dijck J, Đilvesi Đ, Dippel D, Dizdarevic K, Donoghue E, Duek O, Dulière GL, Dzeko A, Eapen G, Emery CA, English S, Esser P, Ezer E, Fabricius M, Feng J, Fergusson D, Figaji A, Fleming J, Foks K, Francony G, Freedman S, Freo U, Frisvold SK, Gagnon I, Galanaud D, Gantner D, Giraud B, Glocker B, Golubovic J, Gómez López PA, Gordon WA, Gradisek P, Gravel J, Griesdale D, Grossi F, Haagsma JA, Håberg AK, Haitsma I, van Hecke W, Helbok R, Helseth E, van Heugten C, Hoedemaekers C, Höfer S, Horton L, Hui J, Huijben JA, Hutchinson PJ, Jacobs B, van der Jagt M, Jankowski S, Janssens K, Jelaca B, Jones KM, Kamnitsas K, Kaps R, Karan M, Katila A, Kaukonen KM, de Keyser V, Kivisaari R, Kolias AG, Kolumbán B, Kolundžija K, Kondziella D, Koskinen LO, Kovács N, Kramer A, Kutsogiannis D, Kyprianou T, Lagares A, Lamontagne F, Latini R, Lauzier F, Lazar I, Ledig C, Lefering R, Legrand V, Levi L, Lightfoot R, Lozano A, MacDonald S, Major S, Manara A, Manhes P, Maréchal H, Martino C, Masala A, Masson S, Mattern J, McFadyen B, McMahon C, Meade M, Melegh B, Menovsky T, Moore L, Morgado Correia M, Morganti-Kossmann MC, Muehlan H, Mukherjee P, Murray L, van der Naalt J, Negru A, Nelson D, Nieboer D, Noirhomme Q, Nyirádi J, Oddo M, Okonkwo DO, Oldenbeuving AW, Ortolano F, Osmond M, Payen JF, Perlbarg V, Persona P, Pichon N, Piippo-Karjalainen A, Pili-Floury S, Pirinen M, Ple H, Poca MA, Posti J, van Praag D, Ptito A, Radoi A, Ragauskas A, Raj R, Real RGL, Reed N, Rhodes J, Robertson C, Rocka S, Røe C, Røise O, Roks G, Rosand J, Rosenfeld JV, Rosenlund C, Rosenthal G, Rossi S, Rueckert D, de Ruiter GCW, Sacchi M, Sahakian BJ, Sahuquillo J, Sakowitz O, Salvato G, Sánchez-Porras R, Sándor J, Sangha G, Schäfer N, Schmidt S, Schneider KJ, Schnyer D, Schöhl H, Schoonman GG, Schou RF, Sir Ö, Skandsen T, Smeets D, Sorinola A, Stamatakis E, Stevanovic A, Stevens RD, Sundström N, Taccone FS, Takala R, Tanskanen P, Taylor MS, Telgmann R, Temkin N, Teodorani G, Thomas M, Tolias CM, Trapani T, Turgeon A, Vajkoczy P, Valadka AB, Valeinis E, Vallance S, Vámos Z, Vargiolu A, Vega E, Verheyden J, Vik A, Vilcinis R, Vleggeert-Lankamp C, Vogt L, Volovici V, Voormolen DC, Vulekovic P, Vande Vyvere T, van Waesberghe J, Wessels L, Wildschut E, Williams G, Winkler MKL, Wolf S, Wood G, Xirouchaki N, Younsi A, Zaaroor M, Zelinkova V, Zemek R, Zumbo F. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017;16(12):987–1048. doi: 10.1016/S1474-4422(17)30371-X.
    1. WHO Violence and Injury Prevention and Disability (VIP) - Neurotrauma [Internet]. 2016 [cited 2020, June 11]. Available from: .
    1. Faul M, Wald MM, Rutland-Brown W, Sullivent EE, Sattin RW. Using a cost-benefit analysis to estimate outcomes of a clinical treatment guideline: testing the Brain Trauma Foundation guidelines for the treatment of severe traumatic brain injury. J Trauma. 2007;63(6):1271–1278. doi: 10.1097/TA.0b013e3181493080.
    1. van Dijck JT, Reith FC, van Erp IA, van Essen TA, Maas AI, Peul WC, de Ruiter GC. Decision making in very severe traumatic brain injury (Glasgow Coma Scale 3-5): a literature review of acute neurosurgical management. J Neurosurg Sci. 2018;62(2):153–177. doi: 10.23736/S0390-5616.17.04255-2.
    1. Hardcastle N, Benzon HA, Vavilala MS. Update on the 2012 guidelines for the management of pediatric traumatic brain injury - information for the anesthesiologist. Paediatr Anaesth. 2014;24(7):703–710. doi: 10.1111/pan.12415.
    1. Bellander BM, Singhrao SK, Ohlsson M, Mattsson P, Svensson M. Complement activation in the human brain after traumatic head injury. J Neurotrauma. 2001;18(12):1295–1311. doi: 10.1089/08977150152725605.
    1. Pischiutta F, Micotti E, Hay JR, Marongiu I, Sammali E, Tolomeo D, Vegliante G, Stocchetti N, Forloni G, de Simoni MG, Stewart W, Zanier ER. Single severe traumatic brain injury produces progressive pathology with ongoing contralateral white matter damage one year after injury. Exp Neurol. 2018;300:167–178. doi: 10.1016/j.expneurol.2017.11.003.
    1. Fann JR, Ribe AR, Pedersen HS, Fenger-Gron M, Christensen J, Benros ME, et al. Long-term risk of dementia among people with traumatic brain injury in Denmark: a population-based observational cohort study. Lancet Psychiatry. 2018;5(5):424–431. doi: 10.1016/S2215-0366(18)30065-8.
    1. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–797. doi: 10.1038/ni.1923.
    1. Kaczorowski SL, Schiding JK, Toth CA, Kochanek PM. Effect of soluble complement receptor-1 on neutrophil accumulation after traumatic brain injury in rats. J Cereb Blood Flow Metab. 1995;15(5):860–864. doi: 10.1038/jcbfm.1995.107.
    1. Yang S, Nakamura T, Hua Y, Keep RF, Younger JG, He Y, Hoff JT, Xi G. The role of complement C3 in intracerebral hemorrhage-induced brain injury. J Cereb Blood Flow Metab. 2006;26(12):1490–1495. doi: 10.1038/sj.jcbfm.9600305.
    1. Sewell DL, Nacewicz B, Liu F, Macvilay S, Erdei A, Lambris JD, Sandor M, Fabry Z. Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist. J Neuroimmunol. 2004;155(1-2):55–63. doi: 10.1016/j.jneuroim.2004.06.003.
    1. Leinhase I, Holers VM, Thurman JM, Harhausen D, Schmidt OI, Pietzcker M, Taha ME, Rittirsch D, Huber-Lang M, Smith WR, Ward PA, Stahel PF. Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation. BMC Neurosci. 2006;7(1):55. doi: 10.1186/1471-2202-7-55.
    1. You Z, Yang J, Takahashi K, Yager PH, Kim HH, Qin T, Stahl GL, Ezekowitz RAB, Carroll MC, Whalen MJ. Reduced tissue damage and improved recovery of motor function after traumatic brain injury in mice deficient in complement component C4. J Cereb Blood Flow Metab. 2007;27(12):1954–1964. doi: 10.1038/sj.jcbfm.9600497.
    1. Takabayashi T, Vannier E, Clark BD, Margolis NH, Dinarello CA, Burke JF, et al. A new biologic role for C3a and C3a desArg: regulation of TNF-alpha and IL-1 beta synthesis. J Immunology (Baltimore, Md: 1950) 1996;156(9):3455–3460.
    1. Wetsel RA. Structure, function and cellular expression of complement anaphylatoxin receptors. Curr Opin Immunol. 1995;7(1):48–53. doi: 10.1016/0952-7915(95)80028-X.
    1. Alawieh A, Langley EF, Weber S, Adkins D, Tomlinson S. Identifying the role of complement in triggering neuroinflammation after traumatic brain injury. J Neurosci. 2018;38(10):2519–2532. doi: 10.1523/JNEUROSCI.2197-17.2018.
    1. Becker P, Zieger S, Rother U, Lutz H, Osswald PM. Complement activation following head and brain trauma. Anaesthesist. 1987;36(6):301–305.
    1. Parry J, Hwang J, Stahel CF, Henderson C, Nadeau J, Stacey S, Beauchamp K, Moore EE, Stahel PF. Soluble terminal complement activation fragment sC5b-9: a new serum biomarker for traumatic brain injury? Eur J Trauma Emerg Surg. 2021;47(5):1491–7. 10.1007/s00068-020-01407-z. Epub 2020 May 25.
    1. Kossmann T, Stahel PF, Morganti-Kossmann MC, Jones JL, Barnum SR. Elevated levels of the complement components C3 and factor B in ventricular cerebrospinal fluid of patients with traumatic brain injury. J Neuroimmunol. 1997;73(1-2):63–69. doi: 10.1016/S0165-5728(96)00164-6.
    1. Stahel PF, Morganti-Kossmann MC, Perez D, Redaelli C, Gloor B, Trentz O, Kossmann T. Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) correlate with blood-brain barrier dysfunction in patients with traumatic brain injury. J Neurotrauma. 2001;18(8):773–781. doi: 10.1089/089771501316919139.
    1. Fluiter K, Opperhuizen AL, Morgan BP, Baas F, Ramaglia V. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. J Immunol. 2014;192(5):2339–2348. doi: 10.4049/jimmunol.1302793.
    1. Ruseva MM, Ramaglia V, Morgan BP, Harris CL. An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice. Proc Natl Acad Sci U S A. 2015;112(46):14319–14324. doi: 10.1073/pnas.1513698112.
    1. Rancan M, Morganti-Kossmann MC, Barnum SR, Saft S, Schmidt OI, Ertel W, Stahel PF. Central nervous system-targeted complement inhibition mediates neuroprotection after closed head injury in transgenic mice. J Cereb Blood Flow Metab. 2003;23(9):1070–1074. doi: 10.1097/01.WCB.0000084250.20114.2C.
    1. Garrett MC, Otten ML, Starke RM, Komotar RJ, Magotti P, Lambris JD, Rynkowski MA, Connolly ES. Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage. Brain Res. 2009;1298:171–177. doi: 10.1016/j.brainres.2009.04.047.
    1. Longhi L, Perego C, Ortolano F, Zanier ER, Bianchi P, Stocchetti N, McIntosh TK, de Simoni MG. C1-inhibitor attenuates neurobehavioral deficits and reduces contusion volume after controlled cortical impact brain injury in mice. Crit Care Med. 2009;37(2):659–665. doi: 10.1097/CCM.0b013e318195998a.
    1. Matsushita M, Thiel S, Jensenius JC, Terai I, Fujita T. Proteolytic activities of two types of mannose-binding lectin-associated serine protease. J Immunol. 2000;165(5):2637–2642. doi: 10.4049/jimmunol.165.5.2637.
    1. Jiang H, Wagner E, Zhang H, Frank MM. Complement 1 inhibitor is a regulator of the alternative complement pathway. J Exp Med. 2001;194(11):1609–1616. doi: 10.1084/jem.194.11.1609.
    1. Gompels MM, Lock RJ. Cinryze (C1-inhibitor) for the treatment of hereditary angioedema. Expert Rev Clin Immunol. 2011;7(5):569–573. doi: 10.1586/eci.11.50.
    1. Caliezi C, Zeerleder S, Redondo M, Regli B, Rothen HU, Zurcher-Zenklusen R, et al. C1-inhibitor in patients with severe sepsis and septic shock: beneficial effect on renal dysfunction. Crit Care Med. 2002;30(8):1722–1728. doi: 10.1097/00003246-200208000-00008.
    1. de Zwaan C, Kleine AH, Diris JH, Glatz JF, Wellens HJ, Strengers PF, Tissing M, Hack CE, van Dieijen-Visser M, Hermens WT. Continuous 48-h C1-inhibitor treatment, following reperfusion therapy, in patients with acute myocardial infarction. Eur Heart J. 2002;23(21):1670–1677. doi: 10.1053/euhj.2002.3191.
    1. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346(jan08 15):e7586. doi: 10.1136/bmj.e7586.
    1. Martinez-Saguer I, Cicardi M, Suffritti C, Rusicke E, Aygoren-Pursun E, Stoll H, et al. Pharmacokinetics of plasma-derived C1-esterase inhibitor after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the PASSION study. Transfusion. 2014;54(6):1552–1561. doi: 10.1111/trf.12501.
    1. Cinryze: EPAR - Public assessment report European Medicines Agency: Science Medicines Health; 2011
    1. Heeres M, Visser T, van Wessem KJ, Koenderman AH, Strengers PF, Koenderman L, et al. The effect of C1-esterase inhibitor on systemic inflammation in trauma patients with a femur fracture - the CAESAR study: study protocol for a randomized controlled trial. Trials. 2011;12(1):223. doi: 10.1186/1745-6215-12-223.
    1. Igonin AA, Protsenko DN, Galstyan GM, Vlasenko AV, Khachatryan NN, Nekhaev IV, Shlyapnikov SA, Lazareva NB, Herscu P. C1-esterase inhibitor infusion increases survival rates for patients with sepsis*. Crit Care Med. 2012;40(3):770–777. doi: 10.1097/CCM.0b013e318236edb8.
    1. Maas AI, Menon DK, Lingsma HF, Pineda JA, Sandel ME, Manley GT. Re-orientation of clinical research in traumatic brain injury: report of an international workshop on comparative effectiveness research. J Neurotrauma. 2012;29(1):32–46. doi: 10.1089/neu.2010.1599.
    1. Maas AI, Harrison-Felix CL, Menon D, Adelson PD, Balkin T, Bullock R, et al. Standardizing data collection in traumatic brain injury. J Neurotrauma. 2011;28(2):177–187. doi: 10.1089/neu.2010.1617.
    1. Zuercher P, Groen JL, Aries MJ, Steyerberg EW, Maas AI, Ercole A, et al. Reliability and validity of the Therapy Intensity Level Scale: analysis of clinimetric properties of a novel approach to assess management of intracranial pressure in traumatic brain injury. J Neurotrauma. 2016;33(19):1768–1774. doi: 10.1089/neu.2015.4266.
    1. Weir J, Steyerberg EW, Butcher I, Lu J, Lingsma HF, McHugh GS, et al. Does the extended Glasgow Outcome Scale add value to the conventional Glasgow Outcome Scale? J Neurotrauma. 2012;29(1):53–58. doi: 10.1089/neu.2011.2137.
    1. Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. J Neurotrauma. 1998;15(8):573–585. doi: 10.1089/neu.1998.15.573.
    1. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet (London, England) 1975;1(7905):480–484. doi: 10.1016/S0140-6736(75)92830-5.
    1. Pettigrew LE, Wilson JT, Teasdale GM. Reliability of ratings on the Glasgow Outcome Scales from in-person and telephone structured interviews. J Head Trauma Rehabil. 2003;18(3):252–258. doi: 10.1097/00001199-200305000-00003.
    1. Wilson JT, Edwards P, Fiddes H, Stewart E, Teasdale GM. Reliability of postal questionnaires for the Glasgow Outcome Scale. J Neurotrauma. 2002;19(9):999–1005. doi: 10.1089/089771502760341910.
    1. von Steinbuchel N, Wilson L, Gibbons H, Hawthorne G, Hofer S, Schmidt S, et al. Quality of Life after Brain Injury (QOLIBRI): scale development and metric properties. J Neurotrauma. 2010;27(7):1167–1185. doi: 10.1089/neu.2009.1076.
    1. von Steinbuechel N, Petersen C, Bullinger M. Assessment of health-related quality of life in persons after traumatic brain injury--development of the Qolibri, a specific measure. Acta Neurochir Suppl. 2005;93:43–49. doi: 10.1007/3-211-27577-0_6.
    1. Ware JE, Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473–483. doi: 10.1097/00005650-199206000-00002.
    1. EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990;16(3):199–208. 10.1016/0168-8510(90)90421-9.
    1. Bouwmans C, Krol M, Severens H, Koopmanschap M, Brouwer W, Hakkaart-van RL. The iMTA Productivity Cost Questionnaire: a standardized instrument for measuring and valuing health-related productivity losses. Value Health. 2015;18(6):753–758. doi: 10.1016/j.jval.2015.05.009.
    1. Taylor FB, Jr, Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86(5):1327–1330. doi: 10.1055/s-0037-1616068.
    1. Majdan M, Mauritz W, Wilbacher I, Brazinova A, Rusnak M, Leitgeb J. Timing and duration of intracranial hypertension versus outcomes after severe traumatic brain injury. Minerva Anestesiol. 2014;80(12):1261–1272.
    1. Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, et al. CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340(mar23 1):c869. doi: 10.1136/bmj.c869.
    1. Lingsma H, Andriessen TM, Haitsema I, Horn J, van der Naalt J, Franschman G, et al. Prognosis in moderate and severe traumatic brain injury: external validation of the IMPACT models and the role of extracranial injuries. J Trauma Acute Care Surg. 2013;74(2):639–646. doi: 10.1097/TA.0b013e31827d602e.
    1. Yadav K, Lewis RJ. Gatekeeping strategies for avoiding false-positive results in clinical trials with many comparisons. Jama. 2017;318(14):1385–1386. doi: 10.1001/jama.2017.13276.
    1. Senn S, Julious S. Measurement in clinical trials: a neglected issue for statisticians? Stat Med. 2009;28(26):3189–3209. doi: 10.1002/sim.3603.
    1. Roozenbeek B, Lingsma HF, Perel P, Edwards P, Roberts I, Murray GD, Maas AI, Steyerberg EW, IMPACT (International Mission on Prognosis and Clinical Trial Design in Traumatic Brain Injury) Study Group. CRASH (Corticosteroid Randomisation After Significant Head Injury) Trial Collaborators The added value of ordinal analysis in clinical trials: an example in traumatic brain injury. Crit Care. 2011;15(3):R127. doi: 10.1186/cc10240.
    1. Wright DW, Clark PL, Pentz RD, Hertzberg V, Kellermann AL. Enrolling subjects by exception from consent versus proxy consent in trauma care research. Ann Emerg Med. 2008;51(4):355–360. doi: 10.1016/j.annemergmed.2007.08.021.
    1. Timmers M, van Duijn D, Kompanje EJO. Is medical scientific research allowed in emergency situations without prior consent from the patient? Ned Tijdschr Geneeskd. 2019;163:D3857.
    1. Kompanje EJ. ‘No time to be lost!’ Ethical considerations on consent for inclusion in emergency pharmacological research in severe traumatic brain injury in the European Union. Sci Eng Ethics. 2007;13(3):371–381. doi: 10.1007/s11948-007-9027-4.
    1. Kompanje EJO, van Dijck J, Chalos V, van den Berg SA, Janssen PM, Nederkoorn PJ, et al. Informed consent procedures for emergency interventional research in patients with traumatic brain injury and ischaemic stroke. Lancet Neurol. 2020;19(12):1033–1042. doi: 10.1016/S1474-4422(20)30276-3.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever