Treatment of autoimmune encephalitis in adults with intravenous immunoglobulin
| ISRCTN | ISRCTN69615004 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN69615004 |
| EudraCT/CTIS number | 2020-004428-40 |
| Secondary identifying numbers | CPMS 47478, UoL001570 |
- Submission date
- 29/09/2020
- Registration date
- 18/03/2021
- Last edited
- 12/12/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Nervous System Diseases
Plain English Summary
Background and study aims
Autoimmune encephalitis is inflammation and swelling of the brain caused by the body’s own immune defence system. It affects about 1 in 100,000 people per year in the UK. The symptoms can include abnormal behaviour, memory problems and seizures. Some patients recover completely, but in others it can cause death or severe disability.
Autoimmune encephalitis is treated with steroids, which reduce inflammation and swelling. If patients are not improving, intravenous immunoglobulin (IVIG) is often also given, usually after a couple of weeks. IVIG is a protein product extracted from the blood of healthy donors. It is given through a drip into a vein each day for 5 days and is used for other diseases that affect the nervous system.
Some doctors think that if IVIG is used from the start of treatment, patients may recover more quickly and have fewer side effects from the illness. While IVIG may help patients it can have side effects, including blood clots or allergic reactions, is expensive and may not help recovery. Currently it is used in about 50% of patients with autoimmune encephalitis. This study is looking at whether or not early treatment with IVIG improves recovery. The aims of the trial are to:
1. To work out whether, in adults with autoimmune encephalitis, early treatment with IVIG leads to a different time to recovery and improves the outcome.
2. To carry out scientific studies to better understand the disease processes in autoimmune encephalitis and see how IVIG affects them.
Who can participate?
Patients aged 16 age or older admitted to hospital with suspected autoimmune encephalitis
What does the study involve?
All patients in the study will receive steroid treatment. This is the standard treatment for autoimmune encephalitis. In addition, participants may be given a short course of IVIG or a product which looks identical (a placebo), but which does not contain the active protein. All participants will undergo regular clinical assessments at the hospital and be asked to complete a series of questionnaires to assess their recovery, and general health and wellbeing.
What are the possible benefits and risks of participating?
There are no guarantees that participating in the study will have any benefits. It is possible patients will benefit from the IVIG treatment and additional monitoring and assessments. The disadvantage in taking part in this study may be the risk of having the side-effects of IVIG (this will not be the case in the group that does not take IVIG). There is also the discomfort of receiving the IVIG through a drip and having a lumbar puncture. There are also risks associated with receiving steroids while pregnant or breastfeeding.
Where is the study run from?
The University of Liverpool and the Centre for Trials Research, Cardiff University (UK)
When is the study starting and how long is it expected to run for?
April 2020 to April 2026
Who is funding the study?
National Institute for Health Research Efficacy and Mechanism Evaluation Programme (UK)
Who is the main contact?
Paula Foscarini-Craggs
EncephIG@Cardiff.ac.uk
Contact information
Public
Neuadd Meirionnydd
Heath Park Way
Cardiff
CF14 4YS
United Kingdom
| Phone | +44 (0)29 206 87522 |
|---|---|
| EncephIG@cardiff.ac.uk |
Study information
| Study design | Multicentre double-blind two-arm placebo-controlled randomized superiority trial, incorporating an internal pilot study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | Intravenous immunoglobulin in autoimmune encephalitis in adults – a randomised double-blind placebo-controlled trial |
| Study acronym | Enceph-IG |
| Study hypothesis | To determine if early treatment with intravenous immunoglobulin (IVIG) changes the time to recovery as measured on the Glasgow Outcome Scale-Extended. |
| Ethics approval(s) |
Approved 25/03/2021, Wales REC 3 (15-19 Cowbridge Road East, Cardiff, CF11 9AB, United Kingdom; +44 (0)29 2078 5741; Wales.REC3@wales.nhs.uk), ref: 21/WA/0050 |
| Condition | Autoimmune encephalitis |
| Intervention | Patients will be randomized 1:1 to IVIG or placebo using random permuted blocks stratified by site, and time from symptom onset. Patients will receive 2 g/kg IVIG or placebo over 5 days. All patients will also receive methylprednisolone 1 g daily intravenously for 5 days, followed by 1 mg/kg bodyweight (maximum dose 60 mg) oral prednisolone daily for 2 weeks. This is followed by a reduction of 10 mg per week until the patient is taking 10 mg daily, and then a further reduction of 1 mg per week until it is stopped. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | IVIG, methylprednisolone, prednisolone |
| Primary outcome measure | Recovery measured using the Glasgow Outcome Scale-Extended (GOSE) every 2 weeks for the first 3 months and then monthly until 12 months post-randomization |
| Secondary outcome measures | 1. Recovery measured using the Glasgow Outcome Scale-Extended (GOSE) at 3 months (all patients), then at 12 months and annually for the duration of the trial for patients who reach those timepoints 2. Neuropsychological outcomes measured using a standard battery of tests (Addenbrooke’s Cognitive Examination III, Weschsler Memory Scale version IV, Wechsler Adult Intelligence (WAIS) test version IV, Confrontational Naming Task, Trail Making Test Parts A and B, Test of Premorbid Functioning, Beck Depression Inventory, Beck Anxiety Inventory, and Perceived Deficits Questionnaire) as well as the Modified Rankin Scale, and The Liverpool Outcome Score. This will be administered at 12 months post-randomization. 3. Health utility and self-rated health measured using EuroQoL five dimension Scale (EQ5D5L) and European Brain Injury Questionnaire (EBIQ) at 3 months, then at 12 months and annually for patients who reach those timepoints 4. Clinical outcomes including adverse events, time to hospital discharge, use of additional immunotherapy rescue treatments, relapse, HDU/ITU admission, seizures, use of ventilator support, and mortality, measured using medical notes and assessment at clinical follow-up appointments at 2 weeks, 3 months and 12 months |
| Overall study start date | 01/04/2020 |
| Overall study end date | 30/04/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 16 Years |
| Sex | Both |
| Target number of participants | 356 |
| Participant inclusion criteria | Current inclusion criteria as of 05/03/2024: 1. Adults (≥16 years) with altered consciousness level AND/OR behavioural change AND/OR working memory deficit AND/OR psychiatric symptoms 2. Persisting for >24 hours and <12 months but no more than 3 months since diagnosis 3. In whom clinician thinks autoimmune encephalitis is the most likely diagnosis 4. CSF polymerase chain reaction (PCR) negative for HSV 1 and 2, and varicella zoster virus 5. CSF microscopy and culture-negative at 48 hours for organisms PLUS two or more of: 1. Seizures (not explained by previously known seizure disorder) OR new movement disorder 2. Cerebrospinal fluid (CSF) white blood cell count 6-1000/mm³ 3. Electroencephalogram consistent with encephalitis 4. Brain magnetic resonance imaging (MRI) or computer tomography (CT) changes consistent with encephalitis (including normal scan) Previous inclusion criteria: 1. Adults (≥16 years) with altered consciousness level AND/OR behavioural change AND/OR working memory deficit AND/OR psychiatric symptoms 2. Persisting for >24 hours and <3 months 3. In whom clinician thinks autoimmune encephalitis is the most likely diagnosis 4. CSF polymerase chain reaction (PCR) negative for HSV 1 and 2, and varicella zoster virus 5. CSF microscopy and culture-negative at 48 hours for organisms PLUS two or more of: 1. Seizures (not explained by previously known seizure disorder) OR new movement disorder 2. Cerebrospinal fluid (CSF) white blood cell count 6-1000/mm³ 3. Electroencephalogram consistent with encephalitis 4. Brain magnetic resonance imaging (MRI) or computer tomography (CT) changes consistent with encephalitis |
| Participant exclusion criteria | 1. No other likely diagnosis 2. Current or recent (within last 6 months) treatment with IVIG 3. Contraindication to IVIG 4. Intolerance of corticosteroids 5. Recent history of gastric ulcers 6. CSF analysis not performed 7. CSF polymerase chain reaction (PCR) positive for any viruses 8. Brain imaging not performed 9. Alternative diagnosis on brain imaging (CT or MRI) 10. Known HIV infection 11. On steroids or other disease-modifying anti-inflammatory therapies 12. Not able to live independently prior to onset of condition |
| Recruitment start date | 11/11/2021 |
| Recruitment end date | 31/10/2024 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
Study participating centres
Liverpool
L9 7LJ
United Kingdom
Bloomsbury
London
NW1 2BU
United Kingdom
Liverpool
L7 8XP
United Kingdom
Glossop Road
Sheffield
S10 2JF
United Kingdom
Oxford
OX3 9DU
United Kingdom
Coventry
CV2 2DX
United Kingdom
Treliske
Truro
TR1 3LJ
United Kingdom
Barrack Road
Exeter
EX2 5DW
United Kingdom
Stoke-on-Trent
ST4 6QG
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Ashford
TW15 3AA
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Fulwood
Preston
PR2 9HT
United Kingdom
Infirmary Square
Leicester
LE1 5WW
United Kingdom
Salford
M6 8HD
United Kingdom
Sponsor information
University/education
-
Liverpool
L69 3BX
England
United Kingdom
| Phone | +44 (0)151 794 8373 |
|---|---|
| sponsor@liverpool.ac.uk | |
| Website | http://www.liv.ac.uk/ |
"ROR" |
https://ror.org/04xs57h96 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Efficacy and Mechanism Evaluation Programme, EME
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/04/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | All publications and presentations relating to the study will be authorised by the TMG and will be in accordance with the trial’s publication policy. In addition to the required final report and monograph for the NIHR EME Programme, we will publish the main study results in international peer-reviewed journals and present at national and international scientific meetings. With the assistance of their collaborators and lay representatives the researchers will disseminate the trial findings to a wide NHS and general audience and vigorously promote uptake of the trial results into clinical care. Any outputs that include data collected through NHS digital or equivalent data provider will include an acknowledgement of the role of the data provider. The aim will be for the results to be revealed initially at the annual Encephalitis Conference, organised by the Encephalitis Society. The results of the study will then be used to inform national and international guidelines on the management of encephalitis. The Liverpool team led the development of the UK national encephalitis guidelines (Solomon et al., 2012), and is currently leading the production of European Guidelines, on behalf of the European Academy of Neurology and the European Society of Clinical Microbiology and Infectious Diseases to be published in 2020. The researchers expect the results of the Enceph-IG study to be available towards the end of 2025 in time for the revision of these guidelines. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from the research team by email to the trial email address, EncephIG@cardiff.ac.uk, and follow the standard CTR data sharing assessment process. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 5.1 | 04/05/2022 | 23/02/2023 | No | No |
| HRA research summary | 28/06/2023 | No | No |
Additional files
Editorial Notes
12/12/2024: The recruitment end date was changed from 31/03/2025 to 31/10/2024.
05/03/2024: The inclusion criteria were updated.
23/02/2023: The following changes were made to the trial record:
1. Protocol added (non peer reviewed).
2. The IPD sharing statement and summary have been changed.
12/11/2021: The recruitment start date has been changed from 01/08/2021 to 11/11/2021.
07/07/2021: The following changes were made to the trial record:
1. The trial website was added.
2. The recruitment start date was changed from 01/07/2021 to 01/08/2021.
3. The trial participating centres Ashford and St Peter’s Hospital NHS Foundation Trust, Sheffield Teaching Hospital NHS Foundation Trust, Oxford University Hospitals NHS Foundation Trust, University Hospitals Coventry and Warwickshire NHS Trust, Royal Cornwall Hospital NHS Trust, Royal Devon and Exeter NHS Trust, University Hospitals of North Midlands NHS Trust, Cambridge University Hospitals NHS Foundation Trust, Ashford and St Peter’s Hospital NHS Foundation Trust, NHS Grampian, Lancashire Teaching Hospital NHS Foundation Trust, University Hospital Leicester NHS Trust, Salford Royal NHS Foundation Trust were added.
13/05/2021: Ethics approval details added.
13/10/2020: Trial's existence confirmed by the NIHR.
