Title: A multicentre randomiSed controlled TRial of IntraVEnous Immunoglobulin (IVIg) versus standard therapy for the treatment of transverse myelitis in adults and children (STRIVE trial)
Funder: Department of Health (England)

Abstract: TM is an immune-mediated disorder of the spinal cord affecting children and adults characterised by a rapid onset of paraplegia or tetraplegia loss of sensation and sphincter disturbance. The attack usually develops over several hours and can progress rapidly to a potentially devastating and life threatening condition. The severity of symptoms depends on the spinal cord level affected where patients with high cervical lesions often require intensive care support to maintain respiratory function. The disease leads to permanent disability in a majority of children and adults. Early recognition diagnosis and treatment are considered integral to the management of this condition. TM is usually accompanied by changes in neuroimaging and a reactive cerebro-spinal fluid analysis which strongly complements the clinical presentation in making a diagnosis of TM as emphasised by the TM Consortium Working Group diagnostic criteria (Neurology 2002;59:499-505). These now universally accepted diagnostic criteria have provided an important framework for clinicians and scientists to improve the diagnosis of TM and also accurately select patients to evaluate interventions. However despite this there currently remains no robust controlled trials for the treatment of TM in children or adults to inform on the optimal treatment of TM.The current management recommendation is largely based on an evidence-based review commissioned by the American Academy of Neurology (Scott et al 2011 Neurology 77(24); 2128-34). Children and adults are now treated with high dose intravenous steroids for 3-7 days to reduce inflammation based on Class IV evidence. Despite the paucity of evidence this remains the most universally accepted mainstay treatment for TM. Plasma exchange (PLEX) is increasingly used in children and adults with acute fulminant central nervous system (CNS) demyelination including TM. The efficacy of PLEX was demonstrated in a small randomized controlled trial in adults with acute central nervous system (CNS) demyelination (including 4 patients with TM) where steroids had failed to induce a remission of symptoms (Weinshenker et al 1999 Ann Neurol 46(6); 878-86). In another study a single centre retrospective analysis of 122 adults with TM some patients were reported to benefit from the addition of PLEX to intravenous steroids (Greenberg et al 2007 Neurology 68(19); 1614-7). However these do not represent sufficient data to determine its efficacy and hence in TM it remains that PLEX is primarily used as rescue therapy when steroids have failed whereas it use as adjunctive therapy with intravenous steroids is still limited. Administering PLEX is technically difficult and is challenging to deliver within the NHS. The procedure mandates a specialist team of clinicians nurses and technicians to administer monitor and evaluate this treatment safely and effectively. Hence although the cost of consumables is relatively low the outlay for filtration units and the service infrastructure to provide this technology more widely may be prohibitive particularly when the condition is rare as in TM (incidence of 3-7 per million cases per year in UK). Another potential therapy for patients with TM is intravenous immunoglobulins (IVIg). In children who do not respond to steroids intravenous immunoglobulin is often used although supporting data are limited to small case series and single case reports (Banwell et al 2007 Lancet Neurol 6; 887-902). Adult practise are likely to reveal a more conservative use of IVIg in TM due to this lack of evidence. IVIg is used increasingly in the management of a range of neurological conditions and its efficacy has been established clearly in randomised controlled trials for some such as Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy (Hughes et al. 2009 Clin Exp Immunol 158 Suppl 1; 34-42). The relevant immune-pathological mechanisms attenuated by IVIg in other neurological disease are likely to be present in TM (Awad and Stuve 2011 Curr Neuropharmacol 9(30); 417-28) providing a strong rationale for its use in the management of acute TM. Its ease of use and potential cost effectiveness over PLEX provide for further support for its evaluation. In this study we propose a multi-centre randomised trial to evaluate if IVIg added early within disease onset to intravenous steroids is beneficial in TM. To perform this trial a group of clinicians clinician-scientists and social scientists specialising in looking after adults and children with immune mediated disorders have teamed up with a well-established clinical trials unit. We have currently identified tertiary neurology centres (11 adult and paediatric) based on geographic distribution established research infrastructure and have investigators with an active track record in recruiting to network supported studies to participate in this study. Patients with a first episode of TM diagnosed by a trial algorithm alongside a standardized core set of investigations will be invited to participate and following consent will be randomised to either treatment arm with all subsequent rescue treatment pathways being standardized. To measure the effectiveness of treatment we have selected measures that will yield reliable data but are easy to administer within the settings of a clinical service to evaluate disease specific and more generic disability. Clinical trial follow-up assessments have also been designed to occur at time points where clinical surveillance would have happened. Importantly we will also evaluate the effect of this treatment on the quality of life in patients and also the economic impact on the NHS. This study will be the first high quality study of IVIg in TM. The trial also aims to generate evidence to inform clinical decision making in the NHS. It will provide good value to the NHS and address healthcare quality of life and productivity costs. In addition this trial will provide bio banked samples from participants for use in biological studies. The study will be practical in nature relatively simple to set up and initiate and rapid to commence recruitment.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL