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

NCT02308982 | Completed Phase 3 DMC

• 1 other identifier: OVG 2014/05
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 25

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.

Conditions

Encephalitis

Keywords

encephalitis; meningoencephalitis; encephalomyelitis; brain inflammation; intravenous immunoglobulin; randomised controlled trial; Central Nervous System Diseases; Central Nervous System Infection

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Brain MRI scan changes

  Up to 6 months after randomization

• Local and systemic adverse events of interest and serious adverse events

  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

  Up to 12 months after randomization

• Presence of auto-antibodies in blood and/or cerebrospinal fluid (CSF)

  Up to 12 Months after randomization

Other Outcomes (4)

• To explore clinically relevant neuroimaging predictors

  Up to 12 Months after randomization

• To explore predictors of neurological outcomes in children with encephalitis

  Up to 12 Months after randomization

• To explore radiological patterns associated with different types of encephalitis

  Up to 12 Months after randomization

Study Arms (2)

Intravenous immunoglobulin

ACTIVE COMPARATOR

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

Drug: Immunoglobulins, Intravenous (Privigen)

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Immunoglobulins, Intravenous (Privigen) DRUG

Also known as: Privigen

Intravenous immunoglobulin

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 6 Weeks - 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (25)

Grampian Health Board

Aberdeen, AB15 6RE, United Kingdom

Location

Birmingham Children's Hospital NHS Foundation Trust

Birmingham, B4 6NH, United Kingdom

Location

Heart of England NHS Foundation Trust

Birmingham, B9 5SS, United Kingdom

Location

University Hospitals Bristol NHS Foundation Trust

Bristol, United Kingdom

Location

Cambridge University Hospitals NHS Foundation Trust

Cambridge, United Kingdom

Location

Tayside Health Board

Dundee, DD1 9SY, United Kingdom

Location

Lothian Health Board

Edinburgh, EH1 3EG, United Kingdom

Location

Hull and East Yorkshire Hospitals NHS Trust

Hull, United Kingdom

Location

Leeds Teaching Hospitals NHS Trust

Leeds, United Kingdom

Location

Alder Hey Children's NHS Foundation Trust

Liverpool, L12 2AP, United Kingdom

Location

Guy's and St Thomas's NHS Foundation Trust

London, SE1 7EH, United Kingdom

Location

Imperial College Healthcare NHS Trust

London, W2 1NY, United Kingdom

Location

Great Ormond Street Hospital

London, WC1N 3JH, United Kingdom

Location

Barts Health NHS Trust

London, United Kingdom

Location

St George's University Hospitals NHS Foundation Trust

London, United Kingdom

Location

Central Manchester University Hospitals NHS Foundation Trust

Manchester, United Kingdom

Location

The Pennine Acute Hospitals NHS Trust

Manchester, United Kingdom

Location

South Tees Hospitals NHS Foundation Trust

Middlesbrough, TS4 3BW, United Kingdom

Location

Nottingham University Hospitals NHS Trust

Nottingham, NG7 2UH, United Kingdom

Location

Oxford University Hospitals NHS Foundation Trust

Oxford, OX9 3DU, United Kingdom

Location

Sheffield Children's NHS Foundation Trust

Sheffield, S10 2TH, United Kingdom

Location

University Hospital Southampton NHS Foundation Trust

Southampton, United Kingdom

Location

University Hospitals of North Midlands NHS Trust

Stoke-on-Trent, United Kingdom

Location

Royal Cornwall Hospitals NHS Trust

Truro, TR1 3 LJ, United Kingdom

Location

York Teaching Hospital NHS Foundation Trust

York, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 27810972 BACKGROUND

• Hill M, Iro M, Sadarangani M, Absoud M, Cantrell L, Chong K, Clark C, Easton A, Gray V, Kneen R, Lim M, Liu X, Pike M, Solomon T, Vincent A, Willis L, Yu LM, Pollard AJ; IgNiTE study team. Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial. BMJ Open. 2023 Nov 9;13(11):e072134. doi: 10.1136/bmjopen-2023-072134.

  PMID: 37945292 DERIVED

Related 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

MeSH Terms

Conditions

Encephalitis; Meningoencephalitis; Encephalomyelitis; Central Nervous System Diseases; Central Nervous System Infections

Interventions

Immunoglobulins; Immunoglobulins, Intravenous

Condition Hierarchy (Ancestors)

Brain Diseases; Nervous System Diseases; Neuroinflammatory Diseases; Central Nervous System Viral Diseases; Infections; Meningitis

Intervention Hierarchy (Ancestors)

Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immunoglobulin G; Immunoglobulin Isotypes; Antibodies

Study Officials

• Andrew J Pollard, FRCPCH, PhD

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2014
• First Posted: December 5, 2014
• Study Start: January 1, 2016
• Primary Completion: September 1, 2022
• Study Completion: September 1, 2022
• Last Updated: March 4, 2024

Record last verified: 2022-09

Locations

GB (25)