Clinical Trial

. 2023 Nov 9;13(11):e072134.

doi: 10.1136/bmjopen-2023-072134.

Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial

Matilda Hill^#¹, Mildred Iro^#², Manish Sadarangani^{2

3

4

5}, Michael Absoud^{6

7}, Liberty Cantrell², Kling Chong⁸, Christopher Clark⁸, Ava Easton^{9

10}, Victoria Gray¹¹, Rachel Kneen^{12

13}, Ming Lim^{6

7}, Xinxue Liu², Michael Pike¹⁴, Tom Solomon^{13

15

16

17}, Angela Vincent^{18

19}, Louise Willis², Ly-Mee Yu²⁰, Andrew J Pollard^{2

3}; IgNiTE study team

Collaborators, Affiliations

Collaborators

IgNiTE study team:
Andrew J Pollard, Ming Lim, Tom Solomon, Rachel Kneen, Michael Absoud, Mike Pike, Manish Sadarangani, Kling Chong, Chris A Clark, Victoria Gray, Mildred Iro, Louise Willis, David Kerr, Sophie Bradshaw, Svetlana Milca, Simon Kerridge, Emma Plested, Yama Mujadidi, Shakeel Herwitker, Mandy Wan, Claire Cameron, Adilia Warris, Federico Martinon-Torres, Mike Bale, Sonia Bale, Alan Percival, Ava Easton, Charles Warlow, Jo Haviland, David Pace, Simon Nadel, Ly-Mee Yu, Meryn Voysey, Xinxue Liu, Liberty Cantrell, Sagida Bibi, Amy Beveridge, Amber Thompson, Daniel O'Connor, Sarosh Irani, Patrick Waters, Lauren Burke, Victoria Gray, Emma Plested, Parvinder Alley, Sanjay Bhate, Paul Heath, Anna Riddell, Archana Desurkar, Elma Stephen, Steve Welch, Paddy McMaster, Alice Jollands, Jay Shetty, Kayal Vijayakumar, Leena Mewasingh, William Whitehouse, Vishal Mehta, John Alexander, John Livingston, Christian de Goede, Dominic Smith, Andrew Collinson

Affiliations

¹ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK matilda.hill@paediatrics.ox.ac.uk.
² Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
³ Department of Paediatrics, University of Oxford, Oxford, UK.
⁴ Vaccine Evaluation Center, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
⁵ Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
⁶ Children's Neurosciences, Evelina London Children's Hospital Neurosciences Department, London, UK.
⁷ Department of Womens and Childrens Health, Faculty of Life Sciences and Medicine, King's College London, London, UK.
⁸ UCL Great Ormond Street Institute of Child Health, London, UK.
⁹ The Encephalitis Society, Malton, North Yorkshire, UK.
¹⁰ Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK.
¹¹ Clinical Health Psychology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
¹² Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
¹³ Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
¹⁴ Department of Paediatric Neurology, Oxford University Hospitals NHS Trust, Oxford, UK.
¹⁵ National Institute for Health Research Health Protection Research Unit in Emerging Zoonotic Infections, University of Liverpool, Liverpool, UK.
¹⁶ Walton Centre NHS Foundation Trust, Liverpool, UK.
¹⁷ The Pandemic Institute, Liverpool, UK.
¹⁸ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹⁹ Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
²⁰ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

^# Contributed equally.

PMID: 37945292
PMCID: PMC10649701
DOI: 10.1136/bmjopen-2023-072134

Clinical Trial

Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial

Matilda Hill et al. BMJ Open. 2023.

. 2023 Nov 9;13(11):e072134.

doi: 10.1136/bmjopen-2023-072134.

Authors

Collaborators

IgNiTE study team:
Andrew J Pollard, Ming Lim, Tom Solomon, Rachel Kneen, Michael Absoud, Mike Pike, Manish Sadarangani, Kling Chong, Chris A Clark, Victoria Gray, Mildred Iro, Louise Willis, David Kerr, Sophie Bradshaw, Svetlana Milca, Simon Kerridge, Emma Plested, Yama Mujadidi, Shakeel Herwitker, Mandy Wan, Claire Cameron, Adilia Warris, Federico Martinon-Torres, Mike Bale, Sonia Bale, Alan Percival, Ava Easton, Charles Warlow, Jo Haviland, David Pace, Simon Nadel, Ly-Mee Yu, Meryn Voysey, Xinxue Liu, Liberty Cantrell, Sagida Bibi, Amy Beveridge, Amber Thompson, Daniel O'Connor, Sarosh Irani, Patrick Waters, Lauren Burke, Victoria Gray, Emma Plested, Parvinder Alley, Sanjay Bhate, Paul Heath, Anna Riddell, Archana Desurkar, Elma Stephen, Steve Welch, Paddy McMaster, Alice Jollands, Jay Shetty, Kayal Vijayakumar, Leena Mewasingh, William Whitehouse, Vishal Mehta, John Alexander, John Livingston, Christian de Goede, Dominic Smith, Andrew Collinson

Affiliations

¹ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK matilda.hill@paediatrics.ox.ac.uk.
² Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
³ Department of Paediatrics, University of Oxford, Oxford, UK.
⁴ Vaccine Evaluation Center, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
⁵ Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
⁶ Children's Neurosciences, Evelina London Children's Hospital Neurosciences Department, London, UK.
⁷ Department of Womens and Childrens Health, Faculty of Life Sciences and Medicine, King's College London, London, UK.
⁸ UCL Great Ormond Street Institute of Child Health, London, UK.
⁹ The Encephalitis Society, Malton, North Yorkshire, UK.
¹⁰ Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK.
¹¹ Clinical Health Psychology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
¹² Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
¹³ Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
¹⁴ Department of Paediatric Neurology, Oxford University Hospitals NHS Trust, Oxford, UK.
¹⁵ National Institute for Health Research Health Protection Research Unit in Emerging Zoonotic Infections, University of Liverpool, Liverpool, UK.
¹⁶ Walton Centre NHS Foundation Trust, Liverpool, UK.
¹⁷ The Pandemic Institute, Liverpool, UK.
¹⁸ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹⁹ Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
²⁰ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

^# Contributed equally.

PMID: 37945292
PMCID: PMC10649701
DOI: 10.1136/bmjopen-2023-072134

Abstract

Objective: To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness.

Design: Phase 3b multicentre, double-blind, randomised placebo-controlled trial.

Setting: Twenty-one hospitals in the UK.

Participants: Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308.

Intervention: Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24-36 hours apart, in addition to standard treatment.

Main outcome measure: The primary outcome was a 'good recovery' at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended.

Secondary outcome measures: The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data.

Results: 18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG.

Conclusions: The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis.

Trial registration number: Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925.

Keywords: clinical trials; developmental neurology & neurodisability; paediatric infectious disease & immunisation; paediatric neurology.

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Conflict of interest statement

Competing interests: MI was a trainee member on the NIHR Efficacy and Mechanism Evaluation Programme Funding Committee from October 2020 to October 2021. MA has received a grant from the NIHR in the last 36 months, for research unrelated to the submitted work. MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines; all funds have been paid to his institute. Ava Easton is Chief Executive of the Encephalitis Society, which has previously received grants from CSL Behring (UK). Ming Lim has received grants from the GOSH charity, Boston Children’s Hospital Research Fund and Action Medical Research in the last 36 months, all for research unrelated to the submitted work. Ming Lim is co-chair of the European Paediatric Neurology Education and Training Board and works for an institution which holds research accounts with Roche (Switzerland), Octapharma (Switzerland) and Novartis (Switzerland). Tom Solomon is supported by the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, NIHR Programme Grant for Applied Research, NIHR Global Health Research on Brain Infections and the European Union’s Horizon 2020 research and innovation program ZikaPLAN. Tom Solomon is a consultant for the MHRA Vaccine Benefit Risk Expert Working Group. Angela Vincent is a consultant for Aspen NewCo Inc and has received honoraria from UCB and Alexion. L-MY was a member of the NIHR Health Technology Assessment Efficient Study Designs from November 2015 to July 2016. Andrew J Pollard is chair of the Department of Health and Social Care’s Joint committee on Vaccines and Immunisation (JCVI) and was a member of WHO’s SAGE until 1 January 2022. Oxford University has entered a partnership with AstraZenenca on COVID-19 vaccines, but Andrew Pollard does not participate in the JCVI COVID-19 committee.

Figures

**Figure 1**
Study flow diagram. IVIG, intravenous immunoglobulin.

See this image and copyright information in PMC

References

1. Tyler KL. Acute viral encephalitis. N Engl J Med 2018;379:557–66. 10.1056/NEJMra1708714 - DOI - PubMed
1. Wang H, Zhao S, Wang S, et al. Global magnitude of encephalitis burden and its evolving pattern over the past 30 years. J Infect 2022;84:777–87. 10.1016/j.jinf.2022.04.026 - DOI - PubMed
1. Dr Julia Granerod AE, Davies DN, Michael DB, et al. Encephalitis: an in-depth review and gap analysis of key variables affecting global disease burden. Encephalitis Society 2022.
1. Britton PN, Dale RC, Blyth CC, et al. Causes and clinical features of childhood encephalitis: A multicenter, prospective cohort study. Clin Infect Dis 2020;70:2517–26. 10.1093/cid/ciz685 - DOI - PubMed
1. Erickson TA, Muscal E, Munoz FM, et al. Infectious and autoimmune causes of encephalitis in children. Pediatrics 2020;145:e20192543. 10.1542/peds.2019-2543 - DOI - PubMed

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Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial

Collaborators

Affiliations

Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

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References

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