Intravenous immunoglobulin treatment for encephalitis in children aged 6 months to 16 years: the IgNiTE RCT

Article history

The research reported in this issue of the journal was funded by the EME programme as award number 12/212/15. The contractual start date was in January 2015. The final report began editorial review in October 2022 and was accepted for publication in July 2023. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The EME editors and production house have tried to ensure the accuracy of the authors’ manuscript and would like to thank the reviewers for their constructive comments on the final manuscript document. However, they do not accept liability for damages or losses arising from material published in this manuscript.

Copyright statement

Copyright © 2024 Iro et al. This work was produced by Iro et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2024 Iro et al.

Background

Encephalitis is a rare condition that can result in serious consequences for those affected and their families. Encephalitis can result from an infection of the brain (infectious encephalitis) or from autoantibodies that affect the brain (immune‐mediated encephalitis), or both. 1 Immune‐mediated disorders, such as acute disseminated encephalomyelitis contribute to a significant proportion of cases where no infective cause is identified. 2 Nonetheless, despite routine investigations, no aetiology is found in up to approximately 40–60% of cases of encephalitis. 2,3

Irrespective of the cause, the final common pathway in the pathophysiology in encephalitis is brain inflammation, which leads to changes in neurological function. Therefore, a paradigm for intervention with the greatest presumptive benefit centres on the early attenuation of the extensive inflammation, which is the primary cause of fatality and neurological sequelae and underpins the pathogenesis of most forms of encephalitis.

Direct evidence of efficacy of intravenous immunoglobulin (IVIG) is suggested by the successful outcomes from both its therapeutic and prophylactic use in enteroviral encephalitis in the immunocompromised and in outbreaks in Southeast and East Asia. There is also evidence from case reports that seem to support the use of IVIG in other infectious causes of encephalitis, including infections with West Nile virus, coxsackie viruses and Mycoplasma pneumoniae, where its use has been associated with rapid improvement and reduced morbidity. The authors of one previous study of IVIG in children with Japanese encephalitis (JE) suggest that IVIG may be an effective treatment for JE and other flaviviral encephalitis due to its anti-inflammatory effects, immune augmentation and neutralisation of the JE virus. 4 However, the result of a Cochrane systematic review of IVIG in infective encephalitis was inconclusive due to the risk of bias and quality of evidence of the included studies. 5

Immunotherapy, often in the form of IVIG, also appears to benefit both adults and children with autoimmune encephalitis, resulting in improved outcomes. Further evidence exists to support the benefit of IVIG in various autoimmune neurological conditions that share similar underlying inflammatory mechanisms to encephalitis, including primary inflammatory myopathies, inflammatory neuropathies and multiple sclerosis. Furthermore, given its disease-modifying properties, there is theoretical evidence of benefit from IVIG treatment even in encephalitis patients who appear to have made an initial full recovery since they can still develop persisting symptoms later.

However, in clinical practice the use of IVIG in encephalitis varies. 6 In the immune-mediated forms of encephalitis, IVIG is typically used after inevitable delay (by weeks in some cases) while alternative diagnoses are being excluded, or until a definitive diagnosis is obtained. In other cases, IVIG is used as a last treatment option where clinical improvement is slow; this is usually after several days from hospital admission. Delay in diagnosis and institution of appropriate treatment in encephalitis may contribute to the high rate of morbidity and mortality, prolonged hospitalisation and associated costs from encephalitis. Given the available evidence of a possible beneficial role of IVIG, there is a strong case for the prospective assessment of the potential role of early intervention with IVIG for all children presenting with evidence of inflammatory encephalitis.

Hypothesis

Our hypothesis was that early treatment with IVIG in addition to standard care could improve neurological outcomes in children with encephalitis.

Study objectives

Encephalitis

In this section, we describe the burden of encephalitis, established treatment options and the role that IVIG might have in the treatment of affected patients.

Encephalitis is a syndrome of neurological dysfunction that results from inflammation of the brain parenchyma. The worldwide annual incidence ranges from 3.5 to 7.4 per 100,000, rising to 16 per 100,000 in children, with the highest incidence in infants under 1 year of age. 7 In England, the incidence of childhood encephalitis is 4.02 per 100,000 per year. 8

Treatments for encephalitis

Following suspicion of an encephalitis diagnosis, antibiotics and antiviral (aciclovir) treatment are usually commenced and subsequently rationalised based on microbiological results and clinical progress. Aciclovir is widely used for the treatment of confirmed herpes simplex and varicella zoster virus encephalitis. For bacterial infections causing encephalitis, an appropriate antibiotic is used, based on microbiological sensitivity testing. For autoimmune encephalitis, treatment strategies including IV methylprednisolone, plasma exchange and IVIG are commonly used.

Literature

The literature review was first carried out in PubMed in 2017 and updated in August 2022 (search terms: ‘intravenous immunoglobulin’ or ‘IVIG’ and ‘encephalitis’).

Summary

Although there is evidence that IVIG benefits some patients with encephalitis, the studies described above have several limitations. Most of the evidence from IVIG use in infectious encephalitis is from single case reports. The largest evidence of IVIG in infectious encephalitis is from a prospective study of children with acute encephalitis complicated by myocarditis, which was a non-randomised study where the study investigators were aware of treatment allocation. 56 In addition, this study was conducted in a developing setting, and it is unclear how the generalisable are the study findings. The evidence from the studies of AIE are compelling. However, the study by Titulaer et al. was not a RCT and enrolled patients received other immunomodulatory treatment alongside IVIG, which makes it impossible to attribute the observed clinical efficacy to IVIG treatment alone. 58 Furthermore, the study by Lee et al. is limited by the small sample size and also lack of a control arm.

The rising use of IVIG in patients with encephalitis in the absence of robust evidence is not without cost implications. In a previously described single-centre study of IVIG use in Australia,79 the total cost of IVIG was US$ 2,595,907 (median $3538/patient, range $544–260,766). In the UK, IVIG costs £18–22 per gram, equivalent to £2100–£3080 per 2 g/kg for a 70-kg patient. 80 Given the high cost associated with IVIG use and its limited availability, and the crucial need to improve outcomes from encephalitis, robust evidence of efficacy from IVIG treatment is imperative.

Trial design

ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE) was a randomised, double-blinded, parallel arm, placebo-controlled study to compare early IVIG treatment with placebo in the treatment of childhood encephalitis in individuals aged 6 months to 16 years.

Research governance

This IgNiTE trial was conducted in compliance with the principles of the Declaration of Helsinki (1996), in full conformity with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines for Good Clinical Practice (CPMP/ICH/135/95 July 1996), the Research Governance Framework and the Medicines for Human Use (Clinical Trial) Regulations 2004. Ethics approval was granted by the UK National Research Ethics Service (NRES) committee (South Central – Oxford A; REC 14/SC/1416). Clinical trial (CT) authorisation granted via the Medicines and Healthcare Products Regulatory Agency (MHRA) notification scheme (Ref: 21584/0337/001-0001). Written approval from local Research and Development (R&D) departments at each participating site was obtained before recruitment was commenced at each site. This trial was sponsored by the University of Oxford and was adopted on the UK children Research Network portfolio (co-adopted by Infectious Diseases and Neurological) UKCRN ID 18993. Quality assurance strategies were in place to ensure compliance with the CT regulations. The trial was registered for an International Standard Randomised Controlled Trial Number (ISRCTN), which was assigned on 24 June 2015 (ISRCTN 15791925). The study was assigned a European Clinical Trials Database number (2014-002997-35) and was registered with ClinicalTrials.gov (identifier NCT 02308982) on 5 December 2014. The trial protocol was published on 3 November 2016. 81 The study database OpenClinica^TM was designed and delivered by the Oxford Vaccine Group Clinical Trials Unit. A Trial Steering Committee (TSC) was set up to oversee the trial. The committee comprised an independent chairperson, an independent patient and public involvement (PPI) member, two independent clinicians, the chief investigator (CI), co-investigators and trial statisticians. The TSC met regularly to monitor and advise on study progress and conduct. An independent Data Monitoring and Ethics Committee (DMEC) was set up to monitor the main outcome measures and to ensure the safety of trial participants. The committee comprised an independent chairperson, a statistician and an expert clinician. The DMEC met regularly throughout the trial to monitor safety, efficacy and the overall conduct of the study.

The protocol was amended after the trial was terminated early to remove endpoints which could not be derived from the data collected and to update the statistical analysis section; this is reflected in this report.

Funding

The study was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (reference 12/212/15). The investigational medicinal product (IMP), IVIG (Privigen) was provided by CSL Behring. The matching placebo (0.9% saline and 0.1% albumin) was manufactured at the Royal Liverpool and Broadgreen Aseptic Manufacturing Unit under its manufacturing license; funds for this were provided by CSL Behring.

Inclusion and exclusion criteria

The inclusion criteria were adapted from the International Encephalitis Consortium case definition. 82

Study procedures

Study flow chart

Figure 1 shows the study flow chart.

FIGURE 1.

Study flow chart

Safety monitoring

Participants were monitored during, and 20 minutes after administration of the study treatment for AEs. The following were reportable in this study:

• AEs and adverse events of special interest (AESIs) occurring in the first 5 days following receipt of each dose of the study drug

• SAEs occurring up until 6 months after randomisation

• serious adverse reactions (SARs) occurring throughout the study period.

An AE was defined as an untoward medical occurrence in a participant that was not necessarily caused by or related to the IMP and was assessed as ‘not related’ or ‘unlikely related’. An adverse reaction (AR) was defined as an untoward and unintended response to the IMP related to any dose administered and was assessed as ‘definitely, likely or possibly related’. An unexpected AR was defined as an AR, the nature and severity of which was not consistent with known information about the IMP. The Summary of Product Characteristics for Privigen was used to assess relatedness of ARs to the study treatment. A SAR was defined as an AE that was both serious and, in the opinion of the reporting Investigator, believed with reasonable probability to be due to one of the trial treatments, based on the information provided. An AESI was defined as any AE of significant scientific, medical, and public interest, relating to an IMP and for which ongoing monitoring and rapid communication by the investigator to the study sponsor could be appropriate.

For each AE, the following information were recorded: description, date of onset and end date, severity and assessment of relatedness to the trial treatment, other suspect drug or device and action taken. The severity was assessed based on the degree to which these affect routine care using the following scale: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death. Assessment of causality (i.e. the relationship between an AE and the trial treatment) was performed by a medically qualified investigator at each study site. AEs or ARs that were assessed to be serious (i.e. fatal, life-threatening, resulting in inpatient hospitalisation or prolongation of hospitalisation, resulted in persistent/significant disability or incapacity, or congenital anomaly/birth defect) were reviewed by a delegated medical doctor and reported to the CI, the study sponsor, and CSL Behring within 24 hours after the study team became aware of the event. All AESIs, SAEs and SARS were followed either until resolution, or the event was considered stable. AESIs included the following: (1) anaphylaxis, (2) new onset seizure or abnormal movements not thought to be due to the encephalitis illness, (3) thromboembolism, (4) aseptic meningitis unrelated to the encephalitis illness, (5) acute renal failure, (6) acute haemolysis and (7) other medically significant event as determined by the investigator. The CI and trial manager provided an annual report of all SAEs and SARs (expected and unexpected), which were distributed to the sponsor, and the Research Ethics Committee (REC). The Sponsor reported all SAEs and SARs to the MHRA as part of the annual Drug Safety Update Report. In addition, throughout the duration of the trial, the DMEC reviewed safety data on an ongoing basis to rule out any significant safety concerns.

Data collection and management

Data were collected by clinical staff using paper-based source documents and were subsequently transcribed onto a secure web-based password-protected eCRF, OpenClinica^TM. The paper and electronic data-collection forms were created in accordance with the requirements of the trial protocol. The eCRF was hosted and maintained by the Oxford Vaccine Group Clinical Trials Unit. All participants were identified using a unique trial-specific number and participant-identifiable data were not included in either the paper or eCRF. At the end of the study, the eCRF system was locked and the data were exported for final analysis after data cleaning. All trial data will be stored and archived in line with the Medicines for Human Use (Clinical Trials) Amended Regulations 2006. All study documents will be retained after the completion or discontinuation of the trial for 3 years after the youngest participant turns 18 years.

Management of the study

The trial was coordinated through the Oxford Vaccine Group, a UK Clinical Research Collaboration registered CTs unit working in collaboration with the Primary Care trials unit at the University of Oxford (registration number: 52). The study coordinating team were responsible for the overall management of the trial and comprised the CI, a study lead doctor and nurse, a trial manager and a quality assurance manager. A study team was set up at each recruiting site to oversee the day-to-day running of the trial and publicise the study within the site. Close communication lines were maintained between individual study teams and the coordinating team. In addition, a Trial Management Group was set up to address and discuss clinical queries and the scientific aspects of the study.

The trial master file (TMF) contained all essential documents for the conduct of the trial: approved trial protocols, regulatory approvals, financial and legal documents, the delegation of trial duties log, copies of approved participant information sheets, participant consent forms, screening logs, standard operating procedures, pharmacy/IMP, safety monitoring, etc. The trial manager was responsible for maintaining the TMF.

Monitoring was performed in line with a trial-specific monitoring plan and comprised remote monitoring of the eCRF data and self-monitoring questionnaires completed by each site. A triggered site visit was necessary for sites that either provided a significant proportion of study data or if queries raised during remote monitoring were not resolved. Review of monitoring activity was conducted by a representative of the study sponsor. After each monitoring visit, the trial manager provided a report summarising the documents that had been reviewed and actions required by the study team which was reviewed by the sponsor and CI.

Recruitment and retention

Patient and public involvement

The Encephalitis Society were actively involved in preparing the proposal for this study. The Society agreed that there is the pressing need for improved treatments to address the serious problem of encephalitis, and fully supported the study. A representative of The Encephalitis Society was on the Trial Management Group and provided a patient-centred research perspective to the study design and conduct. The Encephalitis Society was heavily involved in training research nurses and study recruiters. PPI groups were consulted in the development of the essential documents for the study including the participant information sheet and consent forms. Three PPI representatives with previous personal experiences of encephalitis sat on the TSC and contributed to providing overall oversight of the study. Study update meetings were held to which patients previously affected by encephalitis were invited to share their experiences with study teams, thus highlighting the importance of the study. Preliminary blinded results from the study were presented at various national level meetings and conferences. The Plain language summary of this report was reviewed by the Encephalitis Society. The Encephalitis Society will be actively involved in dissemination of the study findings.

Equality, diversity and inclusion

This trial involved individuals with a rare disease; this patient group is often under-served in clinical research. We sought to enrol all eligible children, regardless of their age, gender or ethnicity. The trial was conducted across 21 NHS sites across the UK, serving different local populations. We involved PPI groups in the design and conduct of this study. Children were actively involved in the consent process; children aged ≥6 years and judged to have sufficient mental capacity were required to give assent.

Sample size

At the time of conception of the IgNiTE trial, there were insufficient data from previous studies for sample size calculation. Detection of at least 20% treatment difference from 43% in the ‘good recovery’ rate (i.e. GOS-E Peds score 2 or lower) by 12 months after randomisation was deemed clinically significant. This was based on the results of a large observational study on autoimmune encephalitis by Titulaer et al. 58 A sample size of 308 (154 per group, including an approximate 10% attrition rate) was needed to achieve 90% power (at 5% level of significance, 2-sided) at detecting a difference in the primary outcome between the study groups.

Statistical methods

The analyses were performed on the intention-to-treat (ITT) population; this included all 18 participants who were randomised. In the analysis of the AEs, the population analysed were the 16 participants who received study treatment.

Since only 20% of participants were recruited before the trial was halted, all analyses are descriptive. Hypothesis testing of outcomes has not been conducted, as these analyses would be severely underpowered. Furthermore, no subgroup comparisons or sensitivity analyses were conducted due to the small number of participants.

Recruitment and participant flow

Recruitment took place between 23 December 2015 and 26 September 2017. During this time, a total of 18 participants were recruited from 21 NHS sites. Appendix 2 shows the recruitment sites and number of participants enrolled from each site. Figure 2 is the CONSORT flow diagram for the trial, which summarises the participant flow through the trial.

FIGURE 2.

CONSORT diagram.

Baseline characteristics

Table 1 summarises the key baseline demographics by treatment arm. The mean age of the participants was 4.09 years (IQR 2.0–11.8), 44% were male, and 89% were of white ethnicity.

Ten participants were randomised to IVIG treatment, and eight participants were randomised to the placebo treatment. Baseline characteristics were balanced between the study groups, although there was a tendency towards lower age in the placebo group and the IVIG arm had slightly more females.

Withdrawal from treatment and from the study

The retention rate of the study was high and comparable between both groups at 12 months after randomisation: 80% (IVIG group) versus 75% (placebo group). Two participants (one in each study group) were withdrawn from the study before receipt of the first dose of study treatment; this was due to one participant being transferred urgently to a non-IgNiTE participating hospital and study treatment being unavailable for another participant. One participant in the IVIG group withdrew consent prior to the 12 months after randomisation time point.

Adherence and compliance with treatment

One participant in the placebo group received only one dose of study treatment due to refusal of the second dose.

Loss to follow-up and missing data

At the 12-month visit for primary endpoint, there were two withdrawals from the IVIG group and one withdrawal and one loss to follow up from the placebo group. The median age for these four participants who had missing data at the 12-month visit for primary endpoint was 8.5 years and 3 (75%) were female. The median age for those with no missing data at the same timepoint was 4.1 years, and 50% were female. Due to small numbers, formal comparison of the two groups was not conducted.

All 18 randomised participants were included in the ITT analysis for primary and secondary outcomes, and all 16 participants who received study treatment were included in the safety analysis.

Primary outcome: GOS-E Peds at 12 months

The primary outcome was assessed using the GOS-E Peds, an outcome scale used to assess level of disability, at 12 months after randomisation. The proportion of participants who made good recovery was similar between both study groups, as shown in Table 2.

Secondary outcomes

Main findings

The IgNiTE trial was the first ever RCT that aimed to evaluate early IVIG treatment in children with encephalitis, irrespective of cause. IgNiTE failed to meet its primary objective due to recruitment difficulties resulting in a small sample size. The study was halted after recruitment of 18 participants due to withdrawal of funding despite proposed alternative strategies to deliver on the study objectives, using a modified protocol. Alternative funding could not be secured; therefore, the trial was ended.

Due to the small sample size, no group comparisons have been conducted and it is impossible to reach any conclusions regarding the efficacy of IVIG in encephalitis. Thus, we comment only on possible trends seen at data analysis. A summary of participant recruitment and flow through the trial is provided by Figure 2.

Results

Interpretation

The findings demonstrate that the morbidity from encephalitis is significant with 28–45% of participants experiencing some degree of disability at 12 months after the acute presentation. It appears that encephalitis patients treated with IVIG have a better quality of life experience and a lesser degree of disability than patients not treated with IVIG, although we cannot exclude the potential influence of missing assessments on these results. IVIG (Privigen) has been extensively researched in other patient populations and its side effect profile is well known. There were no safety concerns relating to IVIG in this study.

Lessons learned

IgNiTE was conducted to a high standard and all outcomes were ascertained appropriately. Notwithstanding the challenges with recruitment, there are several lessons to be learned that could be applied to future trials.

One of the challenges encountered was significant delays with site opening. For trials of rare conditions like encephalitis, a multicentre design is crucial to optimise recruitment. Given the broad clinical spectrum of encephalitis, a multicentre approach also ensures that the study population is truly representative of the real-world cohort of patients since recruitment from only large hospitals is likely to select only those patients with severe disease. While trial set-up can be straightforward, particularly at large tertiary or quaternary hospitals with a lot of experience in conducting RCTs, it can be a more challenging process for smaller hospitals with limited prior involvement in research and the site set-up process can be slow. It had been envisaged that by 21 months from commencing the IgNiTE trial, all planned 30 sites would have opened to recruitment but the delays with site opening meant that this was not achieved. For some sites, this was due to non-availability of research nurses, lack of pharmacy capacity, changes to PI, and delays in obtaining research and development approval. For future trials, such delays should be anticipated, and contingency plans made such as extending the study recruitment period, to account for such delays.

We observed a lower than anticipated incidence of encephalitis. At the time that IgNiTE was set up, there were minimal data on the incidence of encephalitis in the UK. Based on previously published UK data, we estimated the number of paediatric admissions to be 2 per year in district general hospitals and 10 per year in tertiary paediatric hospitals. However, our experience was different with a significantly lower number of actual numbers recruited when compared with the estimates, even during the autumn/winter months when the natural peak in incidence is to be expected. One reason for this could be the disparity between the entry criteria used in the study and the more pragmatic but less stringent approach to making a clinical diagnosis of encephalitis. A proposal to mitigate the recruitment challenge encountered in IgNiTE, which included revision to the sample size to allow recruitment of a smaller but adequately powered sample size, extension to the recruitment period and an increase to the number of participating sites was unsuccessful. For large full-scale trials of rare conditions like childhood encephalitis, incorporating a pilot phase with clear feasibility objectives, clear analytical plans and explicit stop-go criteria is likely to enhance the success of such trials. Furthermore, different methodologies should be explored when designing trials of rare diseases, as improvements in biomarkers increasingly enable sub-phenotyping of conditions, thus further reducing individual disease sample sizes.

For trials of a condition like encephalitis for which the clinical presentation can be non-specific, in-depth consideration should be given to the choice of an appropriate entry criteria. Having a robust set of entry criteria provides guidance on eligibility (and) provides homogeneity in the cohort recruited. This enables a clearer definition of the target population that would benefit from IMP if a treatment effect is established, but can limit generalisability of the study findings to the wider patient population. The impact that having very stringent entry criteria could have on recruitment should be considered. In IgNiTE, a strict entry set based on the International Encephalitis Consortium case definition was used since this approach automatically selects a population that provides the best opportunity to observe a treatment effect. However, this case definition, which is intended for use in research trials, differs from the diagnostic approach routinely used in clinical practice where a lower threshold is applied. This meant that some patients who met the threshold for a clinician diagnosis of encephalitis diagnosis did not meet the criteria for entry into the IgNiTE trial or did not do so within the timelines for administering the first dose of study treatment and were therefore excluded. Given the challenges with recruitment, one approach could have been to use a less stringent set of entry criteria. Although this approach might have contributed to increasing recruitment, given the non-specific presentation of encephalitis, it would have encouraged enrolment of patients with an alternative diagnosis which could dilute the true effect of the study treatment. Assessing the impact of using a set of inclusion criteria that slightly differs from what is routinely used in clinical practice could be undertaken in the pilot phase to inform decisions for the larger trial.

A further consideration for any future trials investigating treatments for childhood encephalitis is how best to optimise the consent rate. The immediate period following hospital admission and/or diagnosis of encephalitis is a sensitive one for the family and especially if the child is admitted to the ICU. Therefore, a longer period of time is likely to be required by the family to consider information about the study to allow them to reach a decision regarding participation, particularly for trials involving an IMP. While it is crucial that families are given sufficient time to decide regarding enrolling their child to a research trial, where there is a time window for recruitment, as was the case in IgNiTE, delays in reaching a decision could mean that the patient becomes ineligible. Gaining the trust of parents/guardians and providing them with a reasonable degree of reassurance regarding the safety of trial procedures are important to mitigate such delays. Several ways to achieve this include maintaining clarity and consistency in the message provided to parents/guardians about a study. This can be difficult to achieve especially on the ICU, where there is a high level of patient/family contact with multiple health professionals, some of whom may not have adequate knowledge of the trial or may have individual biases. One strategy could be for families to be approached only by key individuals who not only have an established relationship with the family but also have adequate knowledge of the study. Other strategies could include branding the trial with key, easy-to-understand messages, and the use of informed consent videos to provide clarity and consistency for families. Furthermore, introducing the study in stages is likely to limit information overload for families which could impact on their understanding of the trial and decision to participate. An approach could be to provide families with a shorter version of the participant information sheet which highlights the main aspects of the study followed by the full version alongside having adequate clinical and research staff support for any queries or concerns that may arise.

For a time-sensitive trial like IgNiTE, where the study treatment has to be administered within a specific time window, it is important to have a large pool of site staff who are trained in the study procedures available at all times to ensure that eligible patients are approached in a timely fashion, since delays could result in potential participants becoming ineligible for the study. The experience from the IgNiTE trial was that most ward staff nurses did not have good clinical practice (GCP) training and due to the clinical demands and workload in the NHS, it can be challenging to achieve in-depth full GCP training upfront. In IgNiTE, we took a pragmatic approach and provided face-to-face GCP training for site staff through the use of study specific training slides, which meant that ad hoc training could be provided to staff to enable them carry out specific study tasks during their clinical shift. Further strategies that could be considered include the use of training videos or other virtual training platforms so that the clinical staff are able to complete the relevant training at a convenient time. Ultimately, incorporating GCP into routine clinical staff training will undoubtedly be beneficial and will increase the pool of clinical staff that are available to support research trials.

For any RCT, it is crucial that clinicians are in a state of both clinical and personal equipoise. In IgNiTE, some participants who met the inclusion criteria were excluded due to prior receipt or planned administration of IVIG as part of routine care. This observation suggests an increased willingness of clinicians to administer IVIG to children with encephalitis and possibly a perceived lack of equipoise in the use of IVIG in encephalitis. For future trials, appointing trial ambassadors at each site to emphasise the importance of the study, and continued, active engagement of clinical teams are fundamental.

The use of placebo as the control arm in RCTs investigating medicinal products has become commonplace and is necessary to provide a clear picture regarding the efficacy of the treatment being studied. Consideration should be given to the choice of placebo. For IgNiTE, the placebo that was used was a 0.9% saline and 0.1% human albumin mix. Addition of albumin was deemed necessary to make the placebo visually identical to IVIG. However, this resulted in a considerable reduction in shelf life from 3 years for 0.9% saline to 6 months for the final placebo product, so batch manufacturing of the placebo in alignment with the demand from sites was necessary to minimise wastage. However, with the slow recruitment, there was wastage of stock held at the individual sites. For future trials of rare conditions that involve use of an IMP, having a central hub to hold a small number of the study treatment which can be subsequently dispensed to sites depending on demand, could be considered. The success of such strategy will hugely rely on having a robust IMP management process and establishing effective communication lines between study teams.

Strengths and limitations

ImmunoglobuliN in the Treatment of Encephalitis was the first RCT that aimed to evaluate the efficacy of IVIG in children with encephalitis, irrespective of aetiology. The strengths include the expertise of the trial management team, the robust study design, and the use of validated outcome measures. Furthermore, the trial design and oversight were heavily informed by patient and public involvement and there was a strong focus on equality, diversity and inclusion, with children being actively involved in the consent process.

The major limitation of the study was that it was unable to answer the important question regarding the role of IVIG in the treatment of childhood encephalitis, due to not achieving the anticipated sample size.

Implications for health care

Up to half of children with encephalitis experience short to long-term difficulties and there is the unmet need to identify strategies to improve outcomes. There is strong observational evidence to support a beneficial role of IVIG for some forms of encephalitis. However, further research is required to assess the efficacy of IVIG in the context of childhood encephalitis of all causes.

Results of a recent single-arm open-label trial in adults suggest that IVIG improved neurological function in patients with autoimmune encephalitis,62 and a randomised double-blind placebo-controlled trial evaluating the efficacy of IVIG in autoimmune encephalitis in adults in the UK is now under way. 84 However, it is uncertain whether the findings of these adult trials could be reliably translated to autoimmune encephalitis in children, and it the role of early IVIG treatment in infective encephalitis in children remains unanswered.

Recommendations for research

Further studies are needed to determine the precise role of IVIG in encephalitis, and if a treatment effect is established, ascertain the optimum dose, timing of administration and cost-effectiveness. Recommendations on aspects of trial design, conduct and delivery that could be considered for future trials have been highlighted. Consideration should be given to adopting a multinational approach to support timely trial delivery.

Contributions of authors

Mildred A Iro (https://orcid.org/0000-0002-9894-6149) (Clinical Research Fellow) was the lead doctor for the trial and prepared the first version, and had input in the design of the trial.

Manish Sadarangani (https://orcid.org/0000-0002-9985-6452) (Paediatric Infectious Diseases and Immunology doctor) is a named investigator on the IgNiTE trial and had input in the design of the trial.

Michael Absoud (https://orcid.org/0000-0002-0577-1897) (Paediatric Neurologist) is a named investigator on the IgNiTE trial and had input in the design of the trial.

Liberty Cantrell (https://orcid.org/0000-0001-5413-7641) (Statistician) conducted analyses for the trial.

Wui K Chong (https://orcid.org/0000-0002-4335-3864) (Neuroradiologist) is a named investigator on the IgNiTE trial.

Christopher Clark (https://orcid.org/0000-0002-8237-6065) (Professor of Neuroimaging) is a named investigator on the IgNiTE trial.

Ava Easton (https://orcid.org/0000-0002-1739-2915) (Chief Executive of The Encephalitis Society) is a named investigator on the IgNiTE trial.

Victoria Gray (https://orcid.org/0000-0002-5828-6369) (Clinical psychologist) is a named investigator on the IgNiTE trial.

Matilda Hill (https://orcid.org/0000-0002-1566-2512) (Paediatric Clinical Research Fellow) prepared subsequent revisions of the manuscript.

Rachael Kneen (https://orcid.org/0000-0002-8729-4122) (Paediatric Neurologist) is a named investigator on the IgNiTE trial and had input in the design of the trial.

Ming Lim (https://orcid.org/0000-0001-7738-8910) (Paediatric Neurologist) is a named investigator on the IgNiTE trial and had input in the design of the trial.

Xinxue Lu (https://orcid.org/0000-0003-1107-0365) (Statistician) conducted analyses for the trial.

Mike Pike (https://orcid.org/0000-0002-9943-3011) (Paediatric Neurologist) conceptualised the trial and is a named investigator on the IgNiTE trial.

Tom Solomon (https://orcid.org/0000-0001-7266-6547) (Professor of Neurology) is a named investigator on the IgNiTE trial and had input in the design of the trial.

Angela Vincent (https://orcid.org/0000-0003-2395-8695) (Professor of Immunology) is a named investigator on the IgNiTE trial.

Louise Willis (https://orcid.org/0000-0003-3115-5964) (Research Nurse) was the lead nurse for the trial.

Ly-Mee Yu (https://orcid.org/0000-0003-0331-7364) (Statistician) is a named investigator on the IgNiTE trial and had input in the design of the trial.

Andrew J Pollard (https://orcid.org/0000-0001-7361-719X) (Professor of Paediatric Infection and Immunity) conceptualised the trial and is a named investigator on the IgNiTE trial.

All authors contributed significantly to the design of the trial, with specific additional contributions from each co-author within their area of expertise. All authors contributed to the manuscript and have approved the final manuscript for publication.

Ignite Study Team

Publications

Hill M, Iro M, Sadarangani M, Absoud M, Cantrell L, Chong K, et al.; IgNiTE study team. Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial. BMJ Open. 2023 Nov 9;13(11):e072134. https://doi.org/10.1136/bmjopen-2023-072134. PMID: 37945292; PMCID: PMC10649701.

Funding

This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (NIHR award ref: 12/212/15) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 6. See the NIHR Funding and Awards website for further award information. CSL Behring provided the study IMP (IVIG) and funded manufacture of placebo and the supply and distribution of IMP and placebo through an Interlaken Award to the Chief Investigator.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to anonymised data may be granted following review.

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that they are stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Ethics statement

This IgNiTE trial was conducted in compliance with the principles of the Declaration of Helsinki (1996), in full conformity with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines for Good Clinical Practice (CPMP/ICH/135/95 July 1996), the Research Governance Framework and the Medicines for Human Use (Clinical Trial) Regulations 2004. Ethics approval was granted by the UK National Research Ethics Service (NRES) committee on 29 December 2014 (South Central – Oxford A; REC 14/SC/1416). Clinical trial authorisation granted via the Medicines and Healthcare Products Regulatory Agency (MHRA) notification scheme (Ref: 21584/0337/001-0001). Written approval from local Research and Development (R&D) departments at each participating site was obtained before recruitment was commenced at each site.

Information governance statement

The University of Oxford is committed to handling all personal information in line with the UK Data Protection Act (2018) and the General Data Protection Regulation (EU GDPR) 2016/679. Under the Data Protection legislation, the University of Oxford is the Data Controller, and you can find out more about how we handle personal data, including how to exercise your individual rights and the contact details for our Data Protection Officer here https://compliance.admin.ox.ac.uk/contact.

Department of Health and Social Care disclaimer

This publication presents independent research commissioned by the National Institute for Health and Care Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, MRC, NIHR Coordinating Centre, the EME programme or the Department of Health and Social Care.

This monograph was published based on current knowledge at the time and date of publication. NIHR is committed to being inclusive and will continually monitor best practice and guidance in relation to terminology and language to ensure that we remain relevant to our stakeholders.

Disclaimer

This manuscript presents independent research. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the MRC, the EME programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the EME programme or the Department of Health and Social Care.