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



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.



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.



NCT02308982, EudraCT201400299735 and ISRCTN15791925; Pre-results.
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
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Oxford Vaccine Group, Department of Paediatrics, University of Oxford and NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.|Department of Paediatrics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.|Vaccine Evaluation Center, BC Children's Hospital Research Institute, University of British Columbia, Vancouver BC, Canada.
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Sadarangani
Department 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.
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Absoud
Department of Radiology, Great Ormond Street Hospital for Children, London, UK.
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Chong
Institute of Child Health, University College London, London, UK.
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Clark
The Encephalitis Society, Malton, North Yorkshire, UK.
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Easton
Psychological services (Paediatrics), Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
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Gray
Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.|Littlewoods Neuroscience Foundation, Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
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Kneen
Department 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.
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Lim
Department of Paediatric Neurology, Oxford University Hospitals NHS Trust, Oxford, UK.
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Pike
Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.|National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK.|Walton Centre NHS Foundation Trust, Liverpool, UK.
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Solomon
Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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Vincent
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
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Willis
Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
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0000-0003-0331-7364
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Yu
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.|Department of Paediatrics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
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Pollard
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002985:Clinical Protocols; D004660:Encephalitis / Q000188:drug therapy* / Q000276:immunology; D050031:Hashimoto Disease / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use*; D007223:Infant; D000069544:Infectious Encephalitis / Q000188:drug therapy / Q000276:immunology; D010372:Pediatrics; D012107:Research Design
D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors
ADEM; GOSE-Peds; autoimmune; encephalitides; immune-mediated