Investigating the Role of Early Intravenous Immunoglobulin Treatment for Children With Encephalitis
- Conditions
- Encephalitis
- Interventions
- Drug: Immunoglobulins, Intravenous (Privigen)Drug: Placebo
- Registration Number
- NCT02308982
- Lead Sponsor
- University of Oxford
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 18
-
6 weeks to 16 years of age (day before 17th birthday) AND
-
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
-
At least two of:
- fever > 38 degrees Celsius within 72 hours before or after presentation to hospital
- brain imaging evidence consistent with encephalitis or immune-mediated encephalopathy that is either new from prior studies or appears acute in onset
- CSF pleocytosis > 4 white blood cells per microlitre
- generalised or partial seizures not fully attributable to a pre-existing seizure disorder
- new onset focal neurological signs (including movement disorders) for > 6 hours
- abnormality on EEG that is consistent with encephalitis and not clearly attributable to another cause AND
-
Parent/guardian/legal representative able to give informed consent
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Intravenous immunoglobulin Immunoglobulins, Intravenous (Privigen) Intravenous immunoglobulin: 1g/kg per day for 2 consecutive days Placebo Placebo Equivalent volume to 1g/kg of IVIG per day for 2 consecutive days
- Primary Outcome Measures
Name Time Method Good recovery", defined by GOS-E-Peds score 2 or lower at 12 months post randomisation Up to 12 Months after randomization Compare neurological outcomes between children with encephalitis who have been treated with IVIG and those who have received matching placebo
- Secondary Outcome Measures
Name Time Method Brain MRI scan changes Up to 6 months after randomization assessment of using lesion resolution presence of new lesions distribution of persisting disease
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 Up to 12 months after randomization 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.
Presence of auto-antibodies in blood and/or cerebrospinal fluid (CSF) Up to 12 Months after randomization Obtain scavenged blood and CSF during the entire study period: prior to and after enrolment; for auto-antibody evaluation.
Local and systemic adverse events of interest and serious adverse events Up to 6 months after randomization 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.
Trial Locations
- Locations (25)
Nottingham University Hospitals NHS Trust
🇬🇧Nottingham, United Kingdom
Grampian Health Board
🇬🇧Aberdeen, United Kingdom
Birmingham Children's Hospital NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
Heart of England NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
University Hospitals Bristol NHS Foundation Trust
🇬🇧Bristol, United Kingdom
Cambridge University Hospitals NHS Foundation Trust
🇬🇧Cambridge, United Kingdom
Tayside Health Board
🇬🇧Dundee, United Kingdom
Leeds Teaching Hospitals NHS Trust
🇬🇧Leeds, United Kingdom
Hull and East Yorkshire Hospitals NHS Trust
🇬🇧Hull, United Kingdom
Lothian Health Board
🇬🇧Edinburgh, United Kingdom
Alder Hey Children's NHS Foundation Trust
🇬🇧Liverpool, United Kingdom
Imperial College Healthcare NHS Trust
🇬🇧London, United Kingdom
Guy's and St Thomas's NHS Foundation Trust
🇬🇧London, United Kingdom
Great Ormond Street Hospital
🇬🇧London, United Kingdom
Barts Health NHS Trust
🇬🇧London, United Kingdom
Central Manchester University Hospitals NHS Foundation Trust
🇬🇧Manchester, United Kingdom
St George's University Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
The Pennine Acute Hospitals NHS Trust
🇬🇧Manchester, United Kingdom
South Tees Hospitals NHS Foundation Trust
🇬🇧Middlesbrough, United Kingdom
Sheffield Children's NHS Foundation Trust
🇬🇧Sheffield, United Kingdom
University Hospital Southampton NHS Foundation Trust
🇬🇧Southampton, United Kingdom
Oxford University Hospitals NHS Foundation Trust
🇬🇧Oxford, United Kingdom
University Hospitals of North Midlands NHS Trust
🇬🇧Stoke on Trent, United Kingdom
York Teaching Hospital NHS Foundation Trust
🇬🇧York, United Kingdom
Royal Cornwall Hospitals NHS Trust
🇬🇧Truro, United Kingdom