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

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

Sponsors

Lead Sponsor: University of Oxford

Collaborator: National Institute for Health Research, United Kingdom
CSL Behring
University of Liverpool
University College London Hospitals
Guy's and St Thomas' NHS Foundation Trust
Liverpool University Hospitals NHS Foundation Trust
Great Ormond Street Hospital for Children NHS Foundation Trust

Source 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.

Overall Status Unknown status
Start Date 2016-01-01
Completion Date 2020-02-01
Primary Completion Date 2019-02-01
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
'Good recovery' defined by a score of 2 or lower, assessed using the Pediatric version of the Glasgow Outcome Scale Extended. 12 months (+/- 4 weeks) post randomisation
Secondary Outcome
Measure Time Frame
Neurological outcomes using age appropriate questionnaires and neuropsychology assessment Up to 12 months post randomisation
Brain MRI scan changes Up to 6 months post randomisation
Local and systemic adverse events of interest and serious adverse events Up to 6 months post randomisation
Presence of auto-antibodies in blood and/or cerebrospinal fluid (CSF) Before and after study treatment
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 post randomisation
Enrollment 308
Condition
Intervention

Intervention Type: Drug

Intervention Name: Immunoglobulins, Intravenous (Privigen)

Arm Group Label: Intravenous immunoglobulin

Other Name: Privigen

Intervention Type: Drug

Intervention Name: Placebo

Arm Group Label: Placebo

Eligibility

Criteria:

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)

Gender:

All

Minimum Age:

6 Weeks

Maximum Age:

16 Years

Healthy Volunteers:

No

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

United Kingdom

Verification Date

2018-10-01

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Intravenous immunoglobulin

Type: Active Comparator

Description: Intravenous immunoglobulin: 1g/kg per day for 2 consecutive days

Label: Placebo

Type: Placebo Comparator

Description: Equivalent volume to 1g/kg of IVIG per day for 2 consecutive days

Acronym IgNiTE
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

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