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Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial.

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posted on 10.06.2019, 13:26 by MD Lyttle, NEA Rainford, C Gamble, S Messahel, A Humphreys, H Hickey, K Woolfall, L Roper, J Noblet, ED Lee, S Potter, P Tate, A Iyer, V Evans, RE Appleton, Paediatric Emergency Research in the United Kingdom & Ireland (PERUKI) collaborative
BACKGROUND: Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus. METHODS: This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894. FINDINGS: Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91-1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). INTERPRETATION: Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus. FUNDING: National Institute for Health Research Health Technology Assessment programme.

Funding

This trial was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (project grant 12/127/134). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The EcLiPSE trial was sponsored by the University of Liverpool (Liverpool, UK) and Alder Hey Children's UK National Health Service (NHS) Foundation Trust (Liverpool, UK). We thank all participating families, all NHS sites and staff who participated in screening and enrolment, the independent members of the trial oversight committees, and staff at the Clinical Trials Research Centre at the University of Liverpool, particularly Nadia Al-Najjar, for Trial Management. The EcLiPSE Trial Management Group is grateful to Rachael Kelly, Managing Editor and the Cochrane Epilepsy Group, University of Liverpool, UK, for assistance with the literature searches for this manuscript.

History

Citation

Lancet, 2019, 393(10186), pp. 2125-2134

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Health Sciences

Version

VoR (Version of Record)

Published in

Lancet

Publisher

Elsevier

eissn

1474-547X

Acceptance date

14/03/2019

Copyright date

2019

Available date

10/06/2019

Publisher version

https://www.sciencedirect.com/science/article/pii/S014067361930724X?via=ihub

Notes

Data will be shared upon request to the Clinical Trials Research Centre (CTRC) University of Liverpool (Liverpool, UK). Requests will be checked for compatibility with participant consent and the CTRC data sharing policy will be followed. The CTRC data sharing policy requires investigator assessment and approval of the request and completion of a data sharing agreement. Anonymised data and a copy of the annotated case report forms will be shared. The data will be available following their inclusion in a planned individual participant data meta-analysis.

Language

en

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