Investigating the Role of Early Intravenous Immunoglobulin Treatment for Children With Encephalitis (IgNiTE)

A Phase III Multi-centre Randomised, Double Blind, Placebo Controlled Trial to Assess the Role of Intravenous Immunoglobulin in the Management of Children With Encephalitis

This is a phase III multi-centre randomised, double blind, placebo controlled trial to assess the role of intravenous immunoglobulin in the treatment of children with encephalitis. The primary objective is to find out whether early use of IVIG treatment improves neurological outcomes of children with encephalitis.

308 children with encephalitis, aged 6 weeks to 16 years will be recruited in 30 hospitals in the United Kingdom. Participants will be randomised to receive two doses of IVIG or matching placebo in addition to other standard treatments, within the first five days of hospital admission.

Each participant will be followed up for 12 months. During this period, information on clinical, radiological and laboratory investigations will be collected. Neurological outcomes will be assessed by the use of questionnaires at 6 and 12 months, and a neuropsychological assessment at 12 months.

Study Overview

• Status: Completed
• Conditions: Encephalitis
• Intervention / Treatment: Drug: Placebo; Drug: Immunoglobulins, Intravenous (Privigen)

Detailed Description

Encephalitis is a syndrome of neurological dysfunction caused by inflammation of the brain parenchyma, resulting in altered mental status, seizures, and/or focal neurologic deficits, usually accompanied by laboratory and radiological evidence of brain inflammation. The worldwide annual incidence of encephalitis ranges from 3.5 to 7.4 per 100,000, rising to 16 per 100,000 in children. In the United Kingdom, Public Health England (formerly the Health Protection Agency) reports an annual rate of 1.5 cases per 100,000 in the general population and 2.8 per 100,000 in children, with the highest incidence in infants under 1 year of age of 8.7 per 100,000.

Despite the use of current standard treatments, mortality of 7-10% and morbidity of up to 50% are still being reported. Encephalitis also imposes a substantial economic and resource burden on healthcare services. Strategies to reduce the disability in patients with encephalitis are therefore required.

There is increasing evidence from case reports of a beneficial role of IVIG treatment in encephalitis. However, in clinical practice, the use of IVIG in encephalitis varies. The variation in practice is in most part due to a lack of class 1 evidence to support the use of IVIG in encephalitis. For 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 a definitive diagnosis is obtained. In other cases, IVIG is used usually as a last treatment option where clinical improvement is slow. Again, this is usually after several days from hospital admission. Delays in the institution of appropriate treatment in encephalitis may contribute to the high rate of morbidity and mortality, prolonged hospitalisation and associated costs from encephalitis. In particular, 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.

This study will fill in the evidence gap on the potential benefit of IVIG in reducing disease burden in children with encephalitis. The trial also aims to generate evidence to inform clinical decision making in the National Health Service (NHS) and provide added value to the NHS by addressing healthcare, quality of life and productivity costs of this expensive and resource limited product.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Aberdeen, United Kingdom, AB15 6RE
    • Grampian Health Board
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital NHS Foundation Trust
  • Birmingham, United Kingdom, B9 5SS
    • Heart of England Nhs Foundation Trust
  • Bristol, United Kingdom
    • University Hospitals Bristol NHS Foundation Trust
  • Cambridge, United Kingdom
    • Cambridge University Hospitals NHS Foundation Trust
  • Dundee, United Kingdom, DD1 9SY
    • Tayside Health Board
  • Edinburgh, United Kingdom, EH1 3EG
    • Lothian Health Board
  • Hull, United Kingdom
    • Hull and East Yorkshire Hospitals NHS Trust
  • Leeds, United Kingdom
    • Leeds Teaching Hospitals NHS Trust
  • Liverpool, United Kingdom, L12 2AP
    • Alder Hey Children's NHS Foundation Trust
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital
  • London, United Kingdom
    • Barts Health NHS Trust
  • London, United Kingdom
    • St George's University Hospitals NHS Foundation Trust
  • London, United Kingdom, W2 1NY
    • Imperial College Healthcare NHS Trust
  • London, United Kingdom, SE1 7EH
    • Guy's and St Thomas's NHS Foundation Trust
  • Manchester, United Kingdom
    • Central Manchester University Hospitals NHS Foundation Trust
  • Manchester, United Kingdom
    • The Pennine Acute Hospitals NHS Trust
  • Middlesbrough, United Kingdom, TS4 3BW
    • South Tees Hospitals NHS Foundation Trust
  • Nottingham, United Kingdom, NG7 2UH
    • Nottingham University Hospitals NHS Trust
  • Oxford, United Kingdom, OX9 3DU
    • Oxford University Hospitals NHS Foundation Trust
  • Sheffield, United Kingdom, S10 2TH
    • Sheffield Children's NHS Foundation Trust
  • Southampton, United Kingdom
    • University Hospital Southampton NHS Foundation Trust
  • Stoke on Trent, United Kingdom
    • University Hospitals of North Midlands NHS Trust
  • Truro, United Kingdom, TR1 3 LJ
    • Royal Cornwall Hospitals NHS Trust
  • York, United Kingdom
    • York Teaching Hospital NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 16 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 6 weeks to 16 years of age (day before 17th birthday) AND
2. Acute (within 24 hours) or sub-acute (between 24 hours and 4 weeks) onset of altered mental state (reduced or altered conscious level, irritability, altered personality or behaviour, lethargy) not attributable to a metabolic cause AND

3. At least two of:

   1. fever > 38 degrees Celsius within 72 hours before or after presentation to hospital
   2. brain imaging evidence consistent with encephalitis or immune-mediated encephalopathy that is either new from prior studies or appears acute in onset
   3. CSF pleocytosis > 4 white blood cells per microlitre
   4. generalised or partial seizures not fully attributable to a pre-existing seizure disorder
   5. new onset focal neurological signs (including movement disorders) for > 6 hours
   6. abnormality on EEG that is consistent with encephalitis and not clearly attributable to another cause AND
4. Parent/guardian/legal representative able to give informed consent

Exclusion Criteria:

• high clinical suspicion of bacterial meningitis or TB meningitis (for example: presence of frankly purulent CSF; CSF WBCs >1000/microlitre; bacteria on Gram stain and/or culture)
• Traumatic brain injury
• Known metabolic encephalopathy
• toxic encephalopathy (i.e. encephalopathy secondary to exposure to intoxicants, including alcohol, prescription or recreational drugs)
• hypertensive encephalopathy/posterior reversible encephalopathy syndrome
• pre-existing demyelinating disorder; pre-existing antibody mediated CNS disorder; pre-existing CSF diversion
• ischaemic or haemorrhagic stroke
• children with a contra-indication to IVIG or albumin (i.e. history of anaphylactic reaction to IVIG or albumin, known IgA deficiency and history of hypersensitisation)
• Known hypercoagulable state
• significant renal impairment defined as GFR of 29mls/min/1.73m2 and below (Chronic Kidney Disease Stage 4)
• Known hyperprolinaemia
• Known to be pregnant
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial
• participants who are being actively followed up in another research trial involving an investigational medicinal product
• Administration of study drug not feasible within 120 hours from hospital admission as determined by the study team
• Any other condition which, in the opinion of the investigator, may interfere with the ability to fulfil study requirements, especially relating to the primary objective of the study (this includes plans to be outside the UK for more than 12 months after enrolment)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intravenous immunoglobulin; Intravenous immunoglobulin: 1g/kg per day for 2 consecutive days	Drug: Immunoglobulins, Intravenous (Privigen); Other Names: Privigen
Placebo Comparator: Placebo; Equivalent volume to 1g/kg of IVIG per day for 2 consecutive days	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Good recovery", defined by GOS-E-Peds score 2 or lower at 12 months post randomisation	Compare neurological outcomes between children with encephalitis who have been treated with IVIG and those who have received matching placebo	Up to 12 Months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain MRI scan changes	assessment of using lesion resolution presence of new lesions distribution of persisting disease	Up to 6 months after randomization
Local and systemic adverse events of interest and serious adverse events	Collection of all serious and non-serious adverse events, including full blood count check 24-48 hours after the second dose of the study drug to monitor for possible haemolysis with IVIG treatment.	Up to 6 months after randomization
Clinical outcomes such as length of hospitalisation, need for intensive care admission, duration of invasive ventilation, frequency of seizures and need for anti-epileptic treatment	Review neurological examination findings as documented in clinical records, identify the need for, and duration of ventilation (for ventilated participants). Also review results of laboratory tests and brain MRI scans which would possibly elongate hospitalisation.	Up to 12 months after randomization
Presence of auto-antibodies in blood and/or cerebrospinal fluid (CSF)	Obtain scavenged blood and CSF during the entire study period: prior to and after enrolment; for auto-antibody evaluation.	Up to 12 Months after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To explore clinically relevant neuroimaging predictors	Correlate MRI findings with the primary and secondary outcomes	Up to 12 Months after randomization
To explore predictors of neurological outcomes in children with encephalitis	Correlate clinical and laboratory parameters with neurological outcomes	Up to 12 Months after randomization
To explore radiological patterns associated with different types of encephalitis	Further analysis that will include using a systematic structured study proforma designed to capture data that would then subsequently be used to aid in: (i) identifying imaging subtypes of different encephalitides for example infectious vs. demyelinating vs. autoimmune (ii) identifying clinically relevant neuroimaging predictors.	Up to 12 Months after randomization
To understand the host inflammatory pathways in encephalitis	(i) Analysis of gene expression in whole blood before and after study treatment (ii) Identification of specific DNA sequence and structural genetic variants in patients with encephalitis	Up to 12 Months after randomization

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: University College London Hospitals; CSL Behring; Guy's and St Thomas' NHS Foundation Trust; Liverpool University Hospitals NHS Foundation Trust; University of Liverpool; National Institute for Health Research, United Kingdom; Great Ormond Street Hospital for Children NHS Foundation Trust
• Investigators: Principal Investigator: Andrew J Pollard, FRCPCH, PhD, University of Oxford

Publications and helpful links

General Publications

• Iro MA, Sadarangani M, Absoud M, Chong WK, Clark CA, Easton A, Gray V, Kneen R, Lim M, Pike M, Solomon T, Vincent A, Willis L, Yu LM, Pollard AJ. ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE): protocol for a multicentre randomised controlled trial. BMJ Open. 2016 Nov 3;6(11):e012356. doi: 10.1136/bmjopen-2016-012356.

Helpful Links

• Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial
• ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE): protocol for a multicentre randomised controlled trial

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Actual): September 1, 2022
• Study Completion (Actual): September 1, 2022

Study Registration Dates

• First Submitted: December 1, 2014
• First Submitted That Met QC Criteria: December 4, 2014
• First Posted (Estimated): December 5, 2014

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Central Nervous System Diseases; randomised controlled trial; intravenous immunoglobulin; encephalitis; meningoencephalitis; encephalomyelitis; brain inflammation; Central Nervous System Infection
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroinflammatory Diseases; Encephalitis; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin
• Other Study ID Numbers: OVG 2014/05