ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE): protocol for a multicentre randomised controlled trial

M A Iro, M Sadarangani, M Absoud, W K Chong, C A Clark, A Easton, V Gray, R Kneen, M Lim, M Pike, T Solomon, A Vincent, L Willis, L-M Yu, A J Pollard, M A Iro, M Sadarangani, M Absoud, W K Chong, C A Clark, A Easton, V Gray, R Kneen, M Lim, M Pike, T Solomon, A Vincent, L Willis, L-M Yu, A J Pollard

Abstract

Introduction: Infectious and immune-mediated encephalitides are important but under-recognised causes of morbidity and mortality in childhood, with a 7% death rate and up to 50% morbidity after prolonged follow-up. There is a theoretical basis for ameliorating the immune response with intravenous immunoglobulin (IVIG), which is supported by empirical evidence of a beneficial response following its use in the treatment of viral and autoimmune encephalitis. In immune-mediated encephalitis, IVIG is often used after a delay (by weeks in some cases), while diagnosis is confirmed. Wider use of IVIG in infectious encephalitis and earlier use in immune-mediated encephalitis could improve outcomes for these conditions. We describe the protocol for the first ever randomised control trial of IVIG treatment for children with all-cause encephalitis.

Methods and analysis: 308 children (6 months to 16 years) with a diagnosis of acute/subacute encephalitis will be recruited in ∼30 UK hospitals and randomised to receive 2 doses (1 g/kg/dose) of either IVIG or matching placebo, in addition to standard treatment. Recruitment will be over a 42-month period and follow-up of each participant will be for 12 months post randomisation. The primary outcome is 'good recovery' (score of 2 or lower on the Glasgow Outcome Score Extended-paediatric version), at 12 months after randomisation. Additional secondary neurological measures will be collected at 4-6 weeks after discharge from acute care and at 6 and 12 months after randomisation. Safety, radiological, other autoimmune and tertiary outcomes will also be assessed.

Ethics and dissemination: This trial has been approved by the UK National Research Ethics committee (South Central-Oxford A; REC 14/SC/1416). Current protocol: V4.0 (10/03/2016). The findings will be presented at national and international meetings and conferences and published in peer-reviewed journals.

Trial registration numbers: NCT02308982, EudraCT201400299735 and ISRCTN15791925; Pre-results.

Keywords: ADEM; GOSE-Peds; autoimmune; encephalitides; immune-mediated.

Conflict of interest statement

CSL Behring have provided the study IMP (IVIG) and funded manufacture of placebo and the supply and distribution of IMP and placebo. AJP reports grants from NIHR EME programme, during the conduct of the study. The University of Oxford and AV hold patents for VGKC-complex antibody tests, licensed to Euroimmun AG, and receive royalties. The neuroimmunology work in the described trial is funded through the MRC/NIHR grant. MA serves on the data safety monitoring board for a study sponsored by Neurim Pharmaceuticals and is on the editorial advisory board for the International Journal of Language and Communication Disorders. MAI and LW report salary from the NIHR EME grant. ML has received consultation fees from CSL Behring, travel grants from Merck Serono and been awarded educational grants to organise meetings by Novartis, Biogen Idec, Merck Serono and Bayer. MS reports grants from Pfizer, outside the submitted work. TS is supported by the National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections at Liverpool. AE, LW, L-MY, MP, MS, RK and WKC have nothing to disclose.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Figures

Figure 1
Figure 1
Flow chart showing process of participant recruitment.

References

    1. Venkatesan A, Tunkel AR, Bloch KC et al. . Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis 2013;57:1114–28. 10.1093/cid/cit458
    1. Granerod J, Cousens S, Davies NW et al. . New estimates of incidence of encephalitis in England. Emerging Infect Dis 2013;19:1455–62. 10.3201/eid1909.130064
    1. Kneen R, Michael BD, Menson E et al. . Management of suspected viral encephalitis in children—Association of British Neurologists and British Paediatric Allergy, Immunology and Infection Group national guidelines. J Infect 2012;64:449–77. 10.1016/j.jinf.2011.11.013
    1. Pillai SC, Hacohen Y, Tantsis E et al. . Infectious and autoantibody-associated encephalitis: clinical features and long-term outcome. Pediatrics 2015;135:e974–84. 10.1542/peds.2014-2702
    1. Graus F, Titulaer MJ, Balu R et al. . A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404. 10.1016/S1474-4422(15)00401-9
    1. Davison KL, Crowcroft NS, Ramsay ME et al. . Viral encephalitis in England, 1989–1998: what did we miss? Emerging Infect Dis 2003;9:234–40. 10.3201/eid0902.020218
    1. Raschilas F, Wolff M, Delatour F et al. . Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 2002;35:254–60. 10.1086/341405
    1. Easton A. Life after encephalitis: a narrative approach. Routledge, 2016.
    1. Dagsdóttir HM, Sigurðardóttir B, Gottfreðsson M et al. . Herpes simplex encephalitis in Iceland 1987–2011. Springerplus 2014;3:524 10.1186/2193-1801-3-524
    1. Michaeli O, Kassis I, Shachor-Meyouhas Y et al. . Long-term motor and cognitive outcome of acute encephalitis. Pediatrics 2014;133:e546–52. 10.1542/peds.2013-3010
    1. Dowell E, Easton A, Solomon T. The Consequences of Encephalitis, Report of a Postal Survey, 2000. Malton: The Encephalitis Society, 2001.
    1. Mailles A, De Broucker T, Costanzo P et al. . Long-term outcome of patients presenting with acute infectious encephalitis of various causes in France. Clin Infect Dis 2012;54:1455–64. 10.1093/cid/cis226
    1. Aygün AD, Kabakuş N, Celik I et al. . Long-term neurological outcome of acute encephalitis. J Trop Pediatr 2001;47:243–7. 10.1093/tropej/47.4.243
    1. Wang SM, Lei HY, Huang MC et al. . Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis. J Clin Virol 2006;37:47–52. 10.1016/j.jcv.2006.05.009
    1. Caramello P, Canta F, Balbiano R et al. . Role of intravenous immunoglobulin administration in Japanese encephalitis. Clin Infect Dis 2006;43:1620–1. 10.1086/509644
    1. Armangue T, Titulaer MJ, Málaga I et al. . Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr 2013;162:850–6.e2. 10.1016/j.jpeds.2012.10.011
    1. Erol I, Ozkale Y, Alkan O et al. . Acute disseminated encephalomyelitis in children and adolescents: a single center experience. Pediatr Neurol 2013;49:266–73. 10.1016/j.pediatrneurol.2013.03.021
    1. Titulaer MJ, McCracken L, Gabilondo I et al. . Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–65. 10.1016/S1474-4422(12)70310-1
    1. Hughes RA, Dalakas MC, Cornblath DR et al. . Clinical applications of intravenous immunoglobulins in neurology. Clin Exp Immunol 2009;158(Suppl 1):34–42. 10.1111/j.1365-2249.2009.04025.x
    1. Dalakas MC. Mechanism of action of intravenous immunoglobulin and therapeutic considerations in the treatment of autoimmune neurologic diseases. Neurology 1998;51(Suppl 5):S2–8. 10.1212/WNL.51.6_Suppl_5.S2
    1. Privigen® Immune Globulin Intravenous (Human), 10% Liquid.” Pharmacy and Therapeutics 36.8 Section 2 2011:2–31.
    1. Beers SR, Wisniewski SR, Garcia-Filion P et al. . Validity of a pediatric version of the Glasgow Outcome Scale-Extended. J Neurotrauma 2012;29:1126–39. 10.1089/neu.2011.2272
    1. Harrison PL, Oakland T. Adaptive behavior assessment system. 2nd edn Minneapolis, MN: Pearson Assessment, 2003.
    1. Young-Lundquist BA, Boccaccini MT, Simpler A. Are self-report measures of adaptive functioning appropriate for those high in psychopathic traits? Behav Sci Law 2012;30:693–709. 10.1002/bsl.2039
    1. Palisano R, Rosenbaum P, Walter S et al. . Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997;39:214–23. 10.1111/j.1469-8749.1997.tb07414.x
    1. Goodman R. The Strengths and Difficulties Questionnaire: a research note. J Child Psychol Psychiatry 1997;38: 581–6. 10.1111/j.1469-7610.1997.tb01545.x
    1. Varni JW, Seid M, Rode CA. The PedsQL: Measurement model for the pediatric quality of life inventory Med Care 1999;37: 126–39.
    1. Varni JW, Burwinkle TM, Seid M et al. . The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity. Ambul Pediatr 2003;3:329–41. 10.1367/1539-4409(2003)003<0329:TPAAPP>;2
    1. Hawcutt DB, Rose AC, Fuerst-Recktenwald S et al. . Points to consider when planning the collection of blood or tissue samples in clinical trials of investigational medicinal products in children, infants and neonates. In: Guide to Paediatric Drug Development and Clinical Research. Karger, Basel, Switzerland 2010:97–110.
    1. Thwaites GE, Chau TT, Farrar JJ. Improving the bacteriological diagnosis of tuberculous meningitis. J Clin Microbiol 2004;42: 378–9. 10.1128/JCM.42.1.378-379.2004

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj