Title: Enceph-IG - Intravenous Immunoglobulin in Autoimmune Encephalitis in Adults: A Randomised Double-Blind Placebo-Controlled Trial
Funder: Medical Research Council

Abstract: Background _x000D_ 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 (fits). Some patients recover completely, but in others it causes death or severe disability._x000D_ _x000D_ 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 by a drip into a vein each day for five days, and is used for other similar diseases. _x000D_ _x000D_ Some doctors think that if IVIG is used from the start of treatment, patients may recover more quickly and have better outcomes. We are therefore faced with a dilemma: on the one hand IVIG may help patients; on the other it is expensive, can have side effects, including blood clots or allergic reactions, and may not help recovery. Currently it is used in about 50% of patients with autoimmune encephalitis. _x000D_ _x000D_ Aims _x000D_ 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._x000D_ 2. To carry out scientific studies to better understand the disease processes in autoimmune encephalitis, and see how IVIG affects them. _x000D_ _x000D_ Design and Methods_x000D_ Our study is a randomised controlled trial of 356 adults: half will receive IVIG, and the other half will receive a placebo (a solution of albumin). It is double blind, meaning neither the patients nor their medical staff will know what they have received. In addition, all patients will receive standard steroid medication. When patients have blood tests and lumbar punctures, some extra samples will be collected for the study._x000D_ _x000D_ Our study will be carried out through hospitals in the Brain Infections UK network. Through this network, and our previous studies, we are confident we will be able to recruit the patients needed. Written, informed consent will be obtained from the patients or a representative._x000D_ _x000D_ Outcome Measures_x000D_ The main outcome is to measure how long it takes a patient to be able to live independently after encephalitis. This is measured through a simple score called the Glasgow Outcome Scale -Extended (GOSE). We will also measure the proportion of patients able to live independently at 3 months and 12 months after first becoming ill. We will also look at markers of the disease, in patient blood and spinal fluid samples, and the effect of IVIG on these._x000D_ _x000D_ Patient and Public Involvement_x000D_ The questions in this research were generated and developed by the Encephalitis Society, a charity which supports people affected by encephalitis. The research plan was then developed with patients, their relatives and carers, through interviews and focus groups. It was modified further following focus group discussions with doctors. The trial steering committee will include a senior representative from the Encephalitis Society, and a recovered patient._x000D_ _x000D_ Dissemination_x000D_ The findings will be published in medical journals and presented at meetings. In addition, as with our previous work we will use innovative methods to engage the wider public with the results of the research.

Lay abstract: Research question_x000D_ _x000D_ In adults with autoimmune encephalitis, does the addition of early intravenous immunoglobulin (IVIG) to the standard corticosteroid treatment give a different recovery time to improve the outcome, and if so, by what mechanism?_x000D_ _x000D_ Background_x000D_ _x000D_ Autoimmune encephalitis, inflammation and swelling of the brain caused by the body’s own immune defence system, affects about 1 in 100,000 people per year in the UK. It is sometimes associated with anti-neuronal antibodies, and is being recognised increasingly. Some patients recover completely, but in others it causes death or severe disability. The disease is treated with steroids. If patients are not improving IVIG is often added, usually after a couple of weeks, but its efficacy is unknown. IVIG is expensive, and can have side effects, including blood clots or allergic reactions. There is currently clinical equipoise about its use._x000D_ _x000D_ Aims and objectives_x000D_ _x000D_ The AIM of this research is to determine whether in adults with autoimmune encephalitis, treatment with early IVIG leads to a different recovery time to improve the outcome, and determine the mechanism by which it might do this._x000D_ _x000D_ The PRIMARY OUTCOME is time from randomisation to achievement of a Glasgow Outcome Scale - Extended (GOSE) of 5 or more; GOSE ranges from 1 (death) to 8 (full recovery), with 5 indicating ability to live independently._x000D_ _x000D_ The CLINICAL OBJECTIVES are to:_x000D_ 1. Conduct a randomised double-blind placebo-controlled trial to address the AIM and PRIMARY OUTCOME._x000D_ 2. Collect cerebrospinal fluid (CSF) and serum from control subjects for comparative mechanistic studies_x000D_ 3. Secondary outcome measures include clinical condition at 3 and 12 months, mortality, adverse events, use of further immunotherapy, neuropsychological outcomes, and subgroup analyses for patients with anti-neuronal antibodies_x000D_ 4. _x000D_ MECHANISTIC OBJECTIVES are to:_x000D_ 1. Establish whether patients with autoimmune encephalitis have aberrant glycosylation of the fragment crystallisable (Fc) region of the immunoglobulin (Ig) G molecule, and how this is affected by IVIG._x000D_ 2. Determine whether a reduction of anti-neuronal antibodies and pro-inflammatory host responses is associated with IVIG treatment, and correlates with clinical improvement._x000D_ _x000D_ Methods_x000D_ _x000D_ A multicentre double-blind placebo-controlled trial of IVIG (2g/kg over 5 days) in 356 adults with autoimmune encephalitis, including:_x000D_ - Stop/Go decision points based on progress at 10 months of the study, and at 6, 12, 18, 24 months of recruitment._x000D_ - an internal pilot after 50 patients to assess recruitment, retention, adherence, contamination, and assumptions around the sample size._x000D_ - _x000D_ Mechanistic studies: compare IgG Fc glycosylation in serum and CSF for patients and controls; look at the effect of IVIG/placebo on glycosylation, on anti-neuronal antibody titres, and on other host response pathways._x000D_ _x000D_ Timelines for delivery_x000D_ _x000D_ 9 months regulatory steps and set up; 53 months patient recruitment; 3 months follow up (12 months for a subgroup); 6 months data analysis, and write-up; 2 months final report and pathways to impact; total 73 months._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ _x000D_ The results will lead to rationalisation of the use of IVIG in autoimmune encephalitis, through NHS England’s Clinical Commissioning Groups. Findings will be published in medical journals, presented at meetings, and disseminated more widely using our innovative methods to engage the wider public.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM