Title: Intravenous immunoglobulin in the management of encephalitis in children
Funder: Department of Health and Social Care

Abstract: Infectious and immune-mediated encephalitides are important but under-recognised causes of neurological morbidity and mortality in childhood, with 7% mortality and up to 50% of survivors reporting deficits after prolonged follow up. There is theoretical and empirical evidence for a beneficial response to intravenous immunoglobulin (IVIG) for both viral and auto-immune aetiologies of childhood encephalitis, but (a) use of this therapy has remained limited in infectious cases (mainly used for outbreaks of enterovirus 71 in the Far East and in the immunocompromised) and (b) it has only been used after inevitable delay (by weeks in some cases) in the immune-mediated conditions while alternative diagnoses are being excluded or a definitive diagnosis is obtained. It is currently unknown whether wider use of IVIG in infectious encephalitis and earlier use in immune-mediated encephalitis could alter the outcome of this group of conditions with a similar clinical presentation. AIMS To determine whether early treatment with IVIG in addition to standard care compared to placebo with standard care improves neurological outcomes in childhood infectious/inflammatory encephalitis DESIGN A multicentre, randomised, double-blind, placebo controlled, two parallel arms clinical trial SETTING 30 paediatric units/hospitals in the UK including: Aberdeen; Belfast; Birmingham Heartlands; Bristol; Cambridge; Cardiff; Dundee; Edinburgh; Glasgow; Great Ormond Street; King’s Health Partners; Leeds; Leicester; Liverpool; Manchester; Newcastle; Nottingham; Oxford; Plymouth; The Royal London; St Mary’s (London); Sheffield; Southampton; Swansea and other hospitals that comprise the UK Childhood CNS demyelinating network. POPULATION Children aged 6 weeks to 16 years of age with acute/subacute infectious or inflammatory encephalitis INTERVENTION BEING EVALUATED Intravenous immunoglobulin (1mg/kg on each of 2 successive days) + standard care CONTROL INTERVENTION Placebo + standard care OUTCOMES Primary Outcome: Performance on the Glasgow Outcome Scale Extended – Pediatric (GOS E-Peds) at 12 months from randomisation Secondary Outcomes: During hospital admission: (1) Duration of ventilation (for ventilated children) (2) Length of hospital stay At 6 months post-randomisation: (3) Performance on the GOS E-Peds (4) MRI brain scan measures At 12 months post randomisation: (5) Number of seizures since discharge (6) Anti-epileptic treatment since discharge (7) Strengths and Difficulties Questionnaire (SDQ) (8) The Adaptive Behavior Assessment System-Second Edition (ABAS-II) (9) Quality of Life by PedsQL (10) Gross Motor Function Classification System (GMFCS) levels (11) Blinded neuropsychological assessment (12) Liverpool Outcome Score (LOS) Exploratory outcomes: (13) Presence of auto-antibodies in sera and CSF obtained before randomisation and at six month follow-up ASSESSMENTS The outcome measures will be obtained at or up to 4 weeks post discharge, at 6 and 12 months +/- 2 weeks from randomisation by a research assessor. All assessments will be carried out blind to group allocation. SAMPLE SIZE There is a near paucity of RCT data from previous studies to estimate sample size for this study. However, to detect at least 20% clinically significant treatment difference from 43% in the “good recovery” rate (i.e. GOS-E-Peds score 2 or lower) by 12 months after randomisation would be deemed clinically significant. This is similar to a large observational study on autoimmune encephalitis by Titulaer et al (2013). Therefore, with 90% power and 5% level of significance (2-sided), a sample size of 308 (154 per group) is required including approximately 10% attrition rate. RANDOMISATION AND BLINDING Allocation (1:1 ratio) will be stratified by region and age group using stratified block randomisation with randomly varying block sizes via a fully validated online randomisation system. Both investigators and participants will be blinded from treatment allocation to minimise both performance and ascertainment biases. STATISTICAL ANALYSIS The primary statistical analysis will be carried out on the basis of ITT. Formal analysis will take place at the end of the study. Interim data summaries will be made available to the IDMC. The primary outcome will be analysed using a Generalised Linear Mixed Effect model(in order to be able to apply the ITT principle, utilising data collected at discharge, 6 and 12 months from randomisation. The model will include treatment group, time, treatment-by-time interaction, and baseline covariates. An unstructured correlation matrix will be used to model the within-subject error correlation structure. An appropriate contrast will be specified to test for treatment efficacy between randomised groups at 12 months. We will, also perform various sensitivity analyses using other imputation methods. Secondary outcomes will be analysed using a similar method or analysis of covariance (for outcomes collected at 12 months only) for continuous data (or equivalent nonparametric methods for non-normal data); and Fisher’s exact test or Chi-squared test for categorical data. The recruitment will run over approximately 42 months (total 60 month project duration). With a recruitment rate of 30%, and the available data on the number of expected cases, 30 sites will allow for optimal recruitment. A full analysis plan will be prepared before recruitment starts SUMMARY OF BENEFITS If early intravenous immunoglobulin is shown to be effective in improving the outcome at 12 months from randomisation, then it will be an important adjuvant treatment which may substantially reduce the burden of long hospital stays, expensive treatment, neurological morbidity and even death. TIMELINE We require 308 children to be recruited within 42 months. With 30 centres this equates to 2 to 3 children/year/site. We plan a start date within 6 months of contract agreement and site set up and total study duration of 5 years, including up to 42 months of recruitment and 12 months of follow up. To achieve this we will obtain the regulatory approvals during contract negotiations, ensure timely recruitment of staff. We will pilot the practical aspects of delivering the intervention, maximising recruitment & retention and data collection in the first 12 months of the study.

Lay abstract: Viral infections and inflammation of the brain caused by the immune system, both of which are described by the term “encephalitis”, are important causes of brain injury and death in childhood, with 7% of those affected dying and up to 50% of survivors reporting problems. A treatment for these conditions using a preparation of natural antibodies made from blood donations (intravenous immunoglobulin, IVIG), has been shown to improve the outcome of a number of inflammatory conditions of the brain and nerves, but has not been widely used in the treatment of viral brain infections and is usually given after some delay in the immune-mediated cases due to the time it takes to establish the diagnosis. There is evidence to support the view that IVIG is beneficial irrespective of the cause of encephalitis. In this study, we plan to test whether use of intravenous immunoglobulin (IVIG), given soon after a child presents to hospital with signs of encephalitis, will improve outcomes. The rest of the treatment will be identical to the normal care that children receive in hospital. To study the potential effect of the treatment we will randomise children who have the condition to either receive a dose of IVIG in addition to standard treatment or matching placebo plus standard treatment, as soon as the diagnosis of encephalitis is made (usually within 48 hours of admission). We will then follow them up carefully during their hospital stay and after discharge to monitor the effects of the treatment and identify any benefits. We aim to establish whether the early administration of IVIG improves the outcome of encephalitis measured at 12 months after hospital admission. We will also assess whether the treatment shortens the duration of intensive care stay or hospital admission, the severity of the illness or the rate or severity of subsequent brain injury in order to evaluate whether this therapy should be used in routine care.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;NEUROLOGICAL