EncephalitisPhase 3IgNiTENCT02308982
Investigating the Role of Early Intravenous Immunoglobulin Treatment for Children With Encephalitis
A Phase 3 study testing Immunoglobulins, Intravenous (Privigen) in people with Encephalitis, run by University of Oxford at 25 sites in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 6 weeks to 16 years
- Conditions the study is for
- Encephalitis
- What is being tested?
- Immunoglobulins, Intravenous (Privigen)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 18 participants
- Where
- 25 sitesUnited Kingdom
- Study dates
- Jan 2016to Sep 2022
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 weeks to 16 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Show all 10Show fewer
- 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
Who cannot join
- 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
Show all 16Show fewer
- 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)
Trial locations and contacts
25 sites in 1 country.
25 sites in 1 country
United Kingdom25 sites
Grampian Health Board
Aberdeen, AB15 6RE
Birmingham Children's Hospital NHS Foundation Trust
Birmingham, B4 6NH
Heart of England NHS Foundation Trust
Birmingham, B9 5SS
University Hospitals Bristol NHS Foundation Trust
Bristol
Cambridge University Hospitals NHS Foundation Trust
Cambridge
Tayside Health Board
Dundee, DD1 9SY
Lothian Health Board
Edinburgh, EH1 3EG
Hull and East Yorkshire Hospitals NHS Trust
Hull
Leeds Teaching Hospitals NHS Trust
Leeds
Alder Hey Children's NHS Foundation Trust
Liverpool, L12 2AP
Guy's and St Thomas's NHS Foundation Trust
London, SE1 7EH
Imperial College Healthcare NHS Trust
London, W2 1NY
Great Ormond Street Hospital
London, WC1N 3JH
Barts Health NHS Trust
London
St George's University Hospitals NHS Foundation Trust
London
Central Manchester University Hospitals NHS Foundation Trust
Manchester
The Pennine Acute Hospitals NHS Trust
Manchester
South Tees Hospitals NHS Foundation Trust
Middlesbrough, TS4 3BW
Nottingham University Hospitals NHS Trust
Nottingham, NG7 2UH
Oxford University Hospitals NHS Foundation Trust
Oxford, OX9 3DU
Sheffield Children's NHS Foundation Trust
Sheffield, S10 2TH
University Hospital Southampton NHS Foundation Trust
Southampton
University Hospitals of North Midlands NHS Trust
Stoke-on-Trent
Royal Cornwall Hospitals NHS Trust
Truro, TR1 3 LJ
York Teaching Hospital NHS Foundation Trust
York
About this study
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
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.
Read the 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.
- Conditions
- Encephalitis
- Being tested
- Immunoglobulins, Intravenous (Privigen), Placebo
- Keywords
- encephalitis, meningoencephalitis, encephalomyelitis, brain inflammation, intravenous immunoglobulin, randomised controlled trial, Central Nervous System Diseases, Central Nervous System Infection
- Medical subject headings
- Encephalitis, Meningoencephalitis, Encephalomyelitis, Central Nervous System Diseases, Central Nervous System Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Immunoglobulins, Intravenous (Privigen)Drug
Also called Privigen
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Intravenous immunoglobulin | Active comparator | Intravenous immunoglobulin: 1g/kg per day for 2 consecutive days Receives: Drug: Immunoglobulins, Intravenous (Privigen) |
| Placebo | Placebo comparator | Equivalent volume to 1g/kg of IVIG per day for 2 consecutive days Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Up to 12 Months after randomization
Secondary outcomes (4)
Brain MRI scan changes
assessment of using lesion resolution presence of new lesions distribution of persisting disease
Measured: Up to 6 months after randomization
Local and systemic adverse events of interest and serious adverse events
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.
Measured: 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
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.
Measured: Up to 12 months after randomization
Presence of auto-antibodies in blood and/or cerebrospinal fluid (CSF)
Obtain scavenged blood and CSF during the entire study period: prior to and after enrolment; for auto-antibody evaluation.
Measured: Up to 12 Months after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Dec 2014 (estimated)
- Study startJan 2016
- Primary completionSep 2022
- Study completionSep 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for EncephalitisStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Collaborators
- 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
- Responsible party
- Sponsor
- Investigators
- Andrew J Pollard, FRCPCH, PhD, Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02308982
- Sponsor's protocol ID
- OVG 2014/05
- Acronym
- IgNiTE
- Status last verified
- Sep 2022
- First submitted
- 1 Dec 2014
- Last updated
- 4 Mar 2024
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 27810972Hill 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.
PubMed 37945292
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02308982
- Acronym / sponsor ID
- IgNiTE / OVG 2014/05
- Conditions
- Encephalitis
- Keywords
- encephalitis, meningoencephalitis, encephalomyelitis, brain inflammation, intravenous immunoglobulin, randomised controlled trial, Central Nervous System Diseases, Central Nervous System Infection
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Collaborators
- 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
- Study start
- Jan 2016
- Primary completion
- Sep 2022 (actual)
- Study completion
- Sep 2022 (actual)
- First posted
- 5 Dec 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Intravenous immunoglobulin | Active comparator | Drug: Immunoglobulins, Intravenous (Privigen)Intravenous immunoglobulin: 1g/kg per day for 2 consecutive days |
| Placebo | Placebo comparator | Drug: PlaceboEquivalent volume to 1g/kg of IVIG per day for 2 consecutive days |
Who may qualify
- Ages
- 6 weeks to 16 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (10 listed)
- 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:
- Parent/guardian/legal representative able to give informed consent
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Immunoglobulins, Intravenous (Privigen)Also: Privigen | Drug | Intravenous immunoglobulin |
| Placebo | Drug | Placebo |
Primary outcome
Good recovery", defined by GOS-E-Peds score 2 or lower at 12 months post randomisation
Time frame: 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
4 secondary outcomes
Brain MRI scan changes
Time frame: Up to 6 months after randomization
Local and systemic adverse events of interest and serious adverse events
Time frame: 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
Time frame: Up to 12 months after randomization
Presence of auto-antibodies in blood and/or cerebrospinal fluid (CSF)
Time frame: Up to 12 Months after randomization
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Mar 2024.
- Background: PubMed 27810972Iro 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.
- Derived from this study: PubMed 37945292Hill 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.
- Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trialLink provided by the sponsor.
- ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE): protocol for a multicentre randomised controlled trialLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andrew J Pollard, FRCPCH, PhD principal investigator
University of Oxford
25 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Immunoglobulins, Intravenous (Privigen) in people with Encephalitis, run by University of Oxford at 25 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 25 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Good recovery", defined by GOS-E-Peds score 2 or lower at 12 months post randomisation (time frame: Up to 12 Months after randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02308982, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2024.