Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial

Page, Emmanuelle Le; Veillard, D.; Laplaud, David‐Axel; Hamonic, Stéphanie; Wardi, Rasha; Lebrun, C.; Zagnoli, Fabien; Wiertlewski, Sandrine; Deburghgraeve, Véronique; Coustans, M.; Edan, Gilles

doi:10.1016/s0140-6736(15)61137-0

“…gov) demonstrated non-inferiority of oral versus intravenous methylprednisolone, provided the dose is high enough (1 g/day for 3 days of either). 26 While not disease-modifying, corticosteroids tend to shorten the duration of the relapse. …”

Section: Acute Relapse Managementmentioning

confidence: 99%

Multiple sclerosis, a treatable disease

Doshi

¹

,

Chataway

²

2016

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This article reviews our current understanding and modern treatment of multiple sclerosis (MS). MS is a disabling condition resulting in devastating social and economic impacts. As MS can affect any part of the central nervous system, the presentation is often diverse; however, there are key features that can be useful in the clinic. We comment on the diagnostic criteria and review the main subtypes of MS, including clinically isolated syndrome, relapsing remitting MS, secondary progressive MS and primary progressive MS. Although the underlying aetiology of MS is still not known, we summarise those with most evidence of association. Finally, we aim to present treatment strategies for managing the acute relapse, disease-modifying therapies and MS symptoms. This review highlights that progressive MS is an area where there is currently a paucity of available diseasemodifying treatments and this will be a major focus for future development.KEYWORDS : Diagnostic criteria , epidemiology , multiple sclerosis , progressive multiple sclerosis , treatments What is multiple sclerosis?Multiple sclerosis (MS) is an acquired disabling neurological disease of young adults, affecting approximately 2.3 million people worldwide. It is most prevalent in North America (140 cases per 100,000) and Europe (108 cases per 100,000); the prevalence is lowest in sub-Saharan Africa (2.1 cases per 100,000) and East Asia (2.2 cases per 100,000).1 Overall, there are approximately 120,000 people with MS in the UK. 2MS is an inflammatory disease of the central nervous system (CNS), which causes a heterogeneous array of symptoms and signs because of differential involvement of motor, sensory, visual and autonomic systems. Optic neuritis (inflammation of the optic nerve), Uhthoff's phenomenon (transient fluctuation or worsening of MS symptoms with a rise in body temperature) and Lhermitte's phenomenon (an abnormal electric-shock like sensation down the spine or limbs on neck flexion) are characteristic of MS.3-5 MS relapses occur because of focal areas ABSTRACTMultiple sclerosis, a treatable disease of demyelination evolving over 24 hours and persisting for days or weeks before generally, though not exclusively, improving.4,6

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“…gov) demonstrated non-inferiority of oral versus intravenous methylprednisolone, provided the dose is high enough (1 g/day for 3 days of either). 26 While not disease-modifying, corticosteroids tend to shorten the duration of the relapse. Plasma exchange is occasionally used, as an adjunctive therapy or alone, if the relapse is rapidly progressive or severe.…”

Section: Acute Relapse Managementmentioning

confidence: 99%

Multiple sclerosis, a treatable disease

Doshi

¹

,

Chataway

²

2017

View full text Add to dashboard Cite

This article reviews our current understanding and modern treatment of multiple sclerosis (MS). MS is a disabling condition resulting in devastating social and economic impacts. As MS can affect any part of the central nervous system, the presentation is often diverse; however, there are key features that can be useful in the clinic. We comment on the diagnostic criteria and review the main subtypes of MS, including clinically isolated syndrome, relapsing remitting MS, secondary progressive MS and primary progressive MS. Although the underlying aetiology of MS is still not known, we summarise those with most evidence of association. Finally, we aim to present treatment strategies for managing the acute relapse, disease-modifying therapies and MS symptoms. This review highlights that progressive MS is an area where there is currently a paucity of available diseasemodifying treatments and this will be a major focus for future development.KEYWORDS : Diagnostic criteria , epidemiology , multiple sclerosis , progressive multiple sclerosis , treatments What is multiple sclerosis?Multiple sclerosis (MS) is an acquired disabling neurological disease of young adults, affecting approximately 2.3 million people worldwide. It is most prevalent in North America (140 cases per 100,000) and Europe (108 cases per 100,000); the prevalence is lowest in sub-Saharan Africa (2.1 cases per 100,000) and East Asia (2.2 cases per 100,000).1 Overall, there are approximately 120,000 people with MS in the UK. 2MS is an inflammatory disease of the central nervous system (CNS), which causes a heterogeneous array of symptoms and signs because of differential involvement of motor, sensory, visual and autonomic systems. Optic neuritis (inflammation of the optic nerve), Uhthoff's phenomenon (transient fluctuation or worsening of MS symptoms with a rise in body temperature) and Lhermitte's phenomenon (an abnormal electric-shock like sensation down the spine or limbs on neck flexion) are characteristic of MS.3-5 MS relapses occur because of focal areas ABSTRACTMultiple sclerosis, a treatable disease of demyelination evolving over 24 hours and persisting for days or weeks before generally, though not exclusively, improving.4,6

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“…17 However, it might increase non-specialists' use of oral corticosteroids without consideration of the indication. It is important to remind that even if not more frequently orally than intravenously, high-dose methylprednisolone can be responsible for adverse effects 15 justifying that the indication must be validated by a neurologist after clinical confirmation of a relapse and the need to treat it with high-dose methylprednisolone. Furthermore, relapses remain a tool of assessing disease-modifying drugs response combined with magnetic resonance imaging (MRI) monitoring of MS activity as illustrated over the last 10 years.…”

Section: What Are the Potential Advantages Of Treating Relapses Of Msmentioning

confidence: 99%

“…The COPOUSEP trial gave a powerful positive response to this eternal question of oral corticosteroids for relapses treatment in MS Indeed, the COPOUSEP trial 15 was the first level 1b study demonstrating non-inferior efficacy and safety of oral versus intravenous high-dose methylprednisolone for relapse treatment in MS, taking into account the potential benefits of the procedure. The methodology resolved the weaknesses of previous trials since it was a randomised, double-blind, non-inferiority trial, adequately powered (200 patients; non-inferiority margin δ of an absolute 15% difference between treatment groups), comparing a similar dosage of methylprednisolone oral versus intravenous, given early after onset of a relapse (less than 2 weeks).…”

mentioning

confidence: 99%

Oral rather than intravenous corticosteroids should be used to treat MS relapses – Yes

Page

¹

,

Edan

²

2017

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The therapeutic arsenal for preventing multiple sclerosis (MS) relapses strongly improved over the last 20 years with more than 10 disease-modifying drugs now available. However, relapses can still occur, requiring treatment with corticosteroids to accelerate recovery. Why were oral corticosteroids not used to treat relapses of MS before 2015?Until recently, the practice usually recommended was to use high doses of methylprednisolone given intravenously, on the basis of four randomised placebocontrolled studies including a total of 193 MS patients, 1-4 and of the Optic Neuritis Treatment Trial (ONTT), 5-7 a much larger study including nearly 450 patients presenting with a first episode of optic neuritis. The results of the ONTT showed that the group receiving methylprednisolone 1 g/day intravenously for 3 days followed by oral tapering recovered more rapidly than the group receiving oral low doses of methylprednisolone (1 mg/kg/day for 14 days). Moreover, the oral group more frequently presented with new relapses during the following 10 years compared with the intravenous and placebo groups. 8 Oral corticosteroids were then considered ineffective and even deleterious for the treatment of MS relapses. But important limitations of the ONTT were identified: it included a population of optic neuritis and not of MS patients, low doses of corticosteroids were used orally versus high doses intravenously, and it was not adequately controlled since control groups did not receive any infusion. The question remained debated and the saga of oral versus intravenous corticosteroids continued with five new randomised controlled trials including 215 MS patients. 9-13 Finally, a meta-analysis 14 published in 2012 pooled the data of these five trials and concluded that there was no significant difference between the oral and intravenous administration of corticosteroids for the treatment of MS relapses but that the results remained insufficient to recommend oral treatment because of lack of power and major methodological limitations such as time from onset of relapse to first dose of up to 1 month (period by which time the resolution phase has already spontaneously started 9,10 ), lack of reliable concealment of allocation or randomisation method, failure to use bioequivalent dosing (oral regimen 10 times lower than the intravenous one in the largest study 9 ) and lack of evidence that an appropriate assessment was conducted. Only one study 12 employed proper equivalence design techniques, but the patients and the clinical assessors of Expanded Disability Status Scale (EDSS) and adverse events (AEs) were not blinded. Moreover, none of these trials evaluated precisely if the tolerance was worse orally than intravenously. So doubts about the use of oral corticosteroids persisted …. 2015:The COPOUSEP trial gave a powerful positive response to this eternal question of oral corticosteroids for relapses treatment in MS Indeed, the COPOUSEP trial 15 was the first level 1b study demonstrating non-inferior efficacy and safety of oral vers...

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Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial

Abstract: French Health Ministry, Ligue Française contre la SEP, Teva.

Cited by 160 publications

References 22 publications

Multiple sclerosis, a treatable disease

Multiple sclerosis, a treatable disease

Multiple sclerosis, a treatable disease

Oral rather than intravenous corticosteroids should be used to treat MS relapses – Yes

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