A multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin compared with standard therapy for the treatment of transverse myelitis in adults and children (STRIVE)

Abstract

Background Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord that affects adults and children and that causes motor, sensory and autonomic dysfunction. There is a prolonged recovery phase, which may continue for many years. Neuromyelitis optica (NMO) is an uncommon relapsing inflammatory central nervous system condition in which TM can be the first presenting symptom. As TM and NMO affect many patients in the prime of their working life, the disorder can impose a significant demand on health resources. There are currently no robust controlled trials in children or adults to inform the optimal treatment of TM. However, treatment with intravenous immunoglobulin (IVIG) is being effectively used in the management of a range of neurological conditions. Although other interventions such as plasma exchange (PLEX) in addition to intravenous (IV) methylprednisolone therapy can be beneficial in TM, PLEX is costly and technically challenging to deliver in the acute setting. IVIG is more readily accessible and less costly. Objective To evaluate whether additional and early treatment with IVIG is of extra benefit in TM compared with standard therapy with IV steroids. Design A multicentre, single-blind, parallel-group randomised controlled trial of IVIG compared with standard therapy for the treatment of TM in adults and children. Participants Patients aged ≥ 1 year diagnosed with either acute first-onset TM or first presentation of NMO. Target recruitment was 170 participants (85 participants per arm). Interventions Participants were randomised 1 : 1 to treatment with IV methylprednisolone only or treatment with IV methylprednisolone plus 2 g/kg of IVIG in divided doses within 5 days of the first commencement of steroid therapy. Main outcome measures Primary outcome measure – American Spinal Injury Association (ASIA) Impairment Scale at 6 months post randomisation, with a good outcome defined by a two-grade change. Secondary and tertiary outcome measures – ASIA motor and sensory scales, Expanded Disability Status Scale, health outcome, quality of life, Client Service Receipt Inventory and International Spinal Cord Injury Pain, Bladder and Bowel Basic Data Sets. Results In total, 26 participants were screened and two were randomised into the study. With the limited sample size, treatment effect could not be determined. However, we identified barriers to accrual that included strict inclusion criteria, the short enrolment window, challenges associated with the use of the ASIA Impairment Scale as an outcome measure and estimation of the incidence of TM. Conclusions The study did not reach the end point and the effect of IVIG in TM/NMO could not be determined. Investigators should be aware of the potential challenges associated with carrying out a rare disease trial with a short enrolment window. The study question is one that still necessitates investigation. Preliminary work to ameliorate the effect of the barriers encountered in this study is vital. Trial registration EudraCT 2014-002335-34, ClinicalTrials.gov NCT02398994 and Current Controlled Trials ISRCTN12127581. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 31. See the NIHR Journals Library website for further project information. Funding was also received from Biotest AG, Germany (supply of IVIG) and the Transverse Myelitis Society (excess research cost to facilitate study initiation).

Recombinant IgG1 Fc hexamers block cytotoxicity and pathological changes in experimental in vitro and rat models of neuromyelitis optica

“…IVIG has been used in various neuro-inflammatory demyelinating disorders including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and myasthenia gravis (Gelfand, 2012; Lünemann et al, 2015; Nguyen et al, 2012; Winkelmann and Zettl, 2012), as well as immune disorders outside of the nervous system such as idiopathic thrombocytopenic purpura (ITP) and Kawasaki disease (Galeotti et al, 2010; Imbach et al, 1981; Katz-Agranov et al, 2015). Several clinical studies, albeit largely anecdotal, support the efficacy of IVIG in NMO (Bakker and Metz, 2004; Elsone et al, 2014; Magraner et al, 2013; Okada et al, 2007; Viswanathan et al, 2015; Wingerchuk, 2013); however, a recent controlled trial of IVIG in NMO transverse myelitis showed no benefit, though the study may have been underpowered (Absoud et al, 2017). We reported a modest, ~50% reduction in pathology in an experimental mouse model of NMO in which IVIG was administered at a dose that produced serum levels comparable to those in IVIG-treated humans (Ratelade et al, 2014).…”

Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies

“…In a retrospective study on 10 NMOSD patients unresponsive to IVMP, IVIgG was effective in 50% of patients [ 87 ]. Unfortunately, a multicenter, single-blind, parallel-group, RCT on IVIG compared to standard therapy for TM treatment in adults and children (STRIVE study [NCT02398994]) was discontinued due to difficulties recruiting patients [ 88 ]. Recently, a retrospective study reported high-dose IVMP plus IVIgG was superior to high-dose of IVMP alone [ 89 ].…”

“…Binding induces an immune response that causes lysis of B cells. NPB-01 (NCT01845584) Intravenous immunoglobulin 400 mg/kg/day for five consecutive days IgG can inactivate auto-reactive T-cells by competing for, and interrupting their interaction with, antigen presenting cells [ 87 , 88 ]. HBM 9161 (NCT04227470) injection, 340 mg or 680 mg weekly administered subcutaneously for a period of 4 weeks.…”

Treatment of myelin oligodendrocyte glycoprotein immunoglobulin G–associated disease

“…Kleiter and colleagues 35 also reported 4 AQP4‐IgG NMOSD attacks treated with IVIG, but therapy was combined with other treatments making interpretation of IVIG alone difficult. Disappointingly STRIVE, a randomized clinical trial, comparing IVMP vs IVMP and IVIG in acute TM, failed to recruit sufficient participants to reach its primary endpoint 44 . Further studies will be required to determine if IVIG is beneficial in MOGAD and other in CNS inflammatory disease.…”

“…35,43 Improvement was noted in 5 of 11 (45.5%) of steroid and PLEXrefractory AQP4-IgG NMOSD relapses (bilateral ON, 4; LETM, 7); with median pretreatment EDSS of 7 (4-9) and posttreatment EDSS of 6.5 (3-9) approximately 2 months later. 43 44 Further studies will be required to determine if IVIG is beneficial in MOGAD and other in CNS inflammatory disease.…”