Clinical trial NCT02308982: Investigating the Role of Early Intravenous Immunoglobulin Treatment for Children With Encephalitis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Encephalitis
Keywords: encephalitis
meningoencephalitis
encephalomyelitis
brain inflammation
intravenous immunoglobulin
randomised controlled trial
Central Nervous System Diseases
Central Nervous System Infection
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: National Institute for Health Research, United Kingdom
name: CSL Behring
name: University of Liverpool
name: University College London Hospitals
name: Guy's and St Thomas' NHS Foundation Trust
name: Liverpool University Hospitals NHS Foundation Trust
name: Great Ormond Street Hospital for Children NHS Foundation Trust
First posted: 2014-12-05
Enrollment: 18
Sex: ALL
Minimum age (years): 6
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Good recovery", defined by GOS-E-Peds score 2 or lower at 12 months post randomisation
timeFrame: Up to 12 Months after randomization
Secondary outcomes:
measure: Brain MRI scan changes
timeFrame: Up to 6 months after randomization
measure: Local and systemic adverse events of interest and serious adverse events
timeFrame: Up to 6 months after randomization
measure: 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
timeFrame: Up to 12 months after randomization
measure: Presence of auto-antibodies in blood and/or cerebrospinal fluid (CSF)
timeFrame: Up to 12 Months after randomization
Other outcomes:
measure: To explore clinically relevant neuroimaging predictors
timeFrame: Up to 12 Months after randomization
measure: To explore predictors of neurological outcomes in children with encephalitis
timeFrame: Up to 12 Months after randomization
measure: To explore radiological patterns associated with different types of encephalitis
timeFrame: Up to 12 Months after randomization
measure: To understand the host inflammatory pathways in encephalitis
timeFrame: Up to 12 Months after randomization
Locations:
city: Aberdeen
country: United Kingdom
facility: Grampian Health Board
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital NHS Foundation Trust
city: Birmingham
country: United Kingdom
facility: Heart of England NHS Foundation Trust
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Dundee
country: United Kingdom
facility: Tayside Health Board
city: Edinburgh
country: United Kingdom
facility: Lothian Health Board
city: Hull
country: United Kingdom
facility: Hull and East Yorkshire Hospitals NHS Trust
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's NHS Foundation Trust
city: London
country: United Kingdom
facility: Guy's and St Thomas's NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: London
country: United Kingdom
facility: St George's University Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Central Manchester University Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Pennine Acute Hospitals NHS Trust
city: Middlesbrough
country: United Kingdom
facility: South Tees Hospitals NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Children's NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
city: Stoke on Trent
country: United Kingdom
facility: University Hospitals of North Midlands NHS Trust
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospitals NHS Trust
city: York
country: United Kingdom
facility: York Teaching Hospital NHS Foundation Trust
Study officials:
affiliation: University of Oxford
name: Andrew J Pollard, FRCPCH, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.