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ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE): protocol for a multicentre randomised controlled trial
  1. M A Iro1,
  2. M Sadarangani1,2,3,
  3. M Absoud4,
  4. W K Chong5,
  5. C A Clark6,
  6. A Easton7,
  7. V Gray8,
  8. R Kneen9,10,
  9. M Lim4,
  10. M Pike11,
  11. T Solomon9,12,13,
  12. A Vincent14,
  13. L Willis1,
  14. L-M Yu15,
  15. A J Pollard1,2
  1. 1Oxford Vaccine Group, Department of Paediatrics, University of Oxford and NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  2. 2Department of Paediatrics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  3. 3Vaccine Evaluation Center, BC Children's Hospital Research Institute, University of British Columbia, Vancouver BC, Canada
  4. 4Department of Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas’ NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London, UK
  5. 5Department of Radiology, Great Ormond Street Hospital for Children, London, UK
  6. 6Institute of Child Health, University College London, London, UK
  7. 7The Encephalitis Society, Malton, North Yorkshire, UK
  8. 8Psychological services (Paediatrics), Alder Hey Children's NHS Foundation Trust, Liverpool, UK
  9. 9Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
  10. 10Littlewoods Neuroscience Foundation, Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
  11. 11Department of Paediatric Neurology, Oxford University Hospitals NHS Trust, Oxford, UK
  12. 12National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK
  13. 13Walton Centre NHS Foundation Trust, Liverpool, UK
  14. 14Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
  15. 15Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
  1. Correspondence to Dr M A Iro; mildred.iro{at}paediatrics.ox.ac.uk

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.

  • ADEM
  • autoimmune
  • encephalitides
  • immune-mediated
  • GOSE-Peds

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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Footnotes

  • MAI and MS joint first authors.

  • Contributors The trial was conceptualised by MP and AJP; with input from ML, MA, RK and TS. MP, MS, RK, TS, WKC, CAC, ML, MA, AV, VG, AE, L-MY and AJP are named investigators on the IgNiTE trial. All authors contributed significantly to the design of the trial, with specific additional contributions from each coauthor within their area of expertise; paediatric neurology (MP, RK, ML, MA), paediatric infectious diseases (MS, AJP), paediatric neuropsychology (VG), neuroimaging (CAC, WKC), neuroimmunology (TS and AV), statistics (L-MY) and patient group (AE). MAI is the lead doctor for the trial and prepared the first version and all subsequent revisions of the manuscript. LW is the lead nurse for the trial. All authors contributed manuscript and have approved the final manuscript for publication.

  • Funding The trial sponsor is Clinical Trials and Research Governance University of Oxford. Funding was received from the Efficacy and Mechanism Evaluation programme, an MRC and NIHR partnership (project number (12/212/15). CSL Behring, via the Interlaken Award, has provided the IVIG that will be used in the trial.

  • Disclaimer The trial sponsor and funders had no role in trial design; collection, management, analysis and interpretation of data; writing of the report; and the decision to submit the report for publication, nor will they have ultimate authority over any of these activities. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the MRC, NHS, NIHR or Department of Health.

  • Competing interests 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.

  • Ethics approval This trial has been approved by the UK National Research Ethics Service (NRES) committee (South Central—Oxford A; REC 14/SC/1416).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data from the study will be made available in the Dryad repository following trial completion. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) licence, which permits others to distribute, remix, adapt, build on this work non-commercially and licence their derivative works on different terms provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0.

  • Study investigators MS, MA, WKC, CAC, AE, VG, RK, ML, MP, TS, AV, L-MY, AJ.

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