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

Sponsor

University of Oxford (Other)

Overall Status

Unknown status

CT.gov ID

NCT02308982

Collaborator

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

308

Enrollment

Locations

Arms

Duration (Months)

12.3

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Encephalitis	Drug: Immunoglobulins, Intravenous (Privigen) Drug: Placebo	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

308 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

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

Primary Purpose:

Treatment

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 Start Date :

Jan 1, 2016

Anticipated Primary Completion Date :

Feb 1, 2019

Anticipated Study Completion Date :

Feb 1, 2020

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

'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 Measures

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]

Other Outcome Measures

Inflammatory cytokines in blood and/or CSF [Before and after study treatment]
Regulatory T cell frequency and function in blood and/or CSF [Before and after study treatment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Weeks to 16 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

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)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Grampian Health Board	Aberdeen	United Kingdom	AB15 6RE
2	Birmingham Children's Hospital NHS Foundation Trust	Birmingham	United Kingdom	B4 6NH
3	Heart of England NHS Foundation Trust	Birmingham	United Kingdom	B9 5SS
4	University Hospitals Bristol NHS Foundation Trust	Bristol	United Kingdom
5	Cambridge University Hospitals NHS Foundation Trust	Cambridge	United Kingdom
6	Tayside Health Board	Dundee	United Kingdom	DD1 9SY
7	Lothian Health Board	Edinburgh	United Kingdom	EH1 3EG
8	Hull and East Yorkshire Hospitals NHS Trust	Hull	United Kingdom
9	Leeds Teaching Hospitals NHS Trust	Leeds	United Kingdom
10	Alder Hey Children's NHS Foundation Trust	Liverpool	United Kingdom	L12 2AP
11	Guy's and St Thomas's NHS Foundation Trust	London	United Kingdom	SE1 7EH
12	Imperial College Healthcare NHS Trust	London	United Kingdom	W2 1NY
13	Great Ormond Street Hospital	London	United Kingdom	WC1N 3JH
14	Barts Health NHS Trust	London	United Kingdom
15	St George's University Hospitals NHS Foundation Trust	London	United Kingdom
16	Central Manchester University Hospitals NHS Foundation Trust	Manchester	United Kingdom
17	The Pennine Acute Hospitals NHS Trust	Manchester	United Kingdom
18	South Tees Hospitals NHS Foundation Trust	Middlesbrough	United Kingdom	TS4 3BW
19	Nottingham University Hospitals NHS Trust	Nottingham	United Kingdom	NG7 2UH
20	Oxford University Hospitals NHS Foundation Trust	Oxford	United Kingdom	OX9 3DU
21	Sheffield Children's NHS Foundation Trust	Sheffield	United Kingdom	S10 2TH
22	University Hospital Southampton NHS Foundation Trust	Southampton	United Kingdom
23	University Hospitals of North Midlands NHS Trust	Stoke on Trent	United Kingdom
24	Royal Cornwall Hospitals NHS Trust	Truro	United Kingdom	TR1 3 LJ
25	York Teaching Hospital NHS Foundation Trust	York	United Kingdom