Abstract
BackgroundConvulsive status epilepticus (CSE) is the most common life-threatening neurological emergency in childhood. These children are also at risk of significant morbidity, with acute and chronic impact on the family and the health and social care systems. The current recommended first-choice, second-line treatment in children aged 6 months and above is intravenous phenytoin (fosphenytoin in the USA), although there is a lack of evidence for its use and it is associated with significant side effects. Emerging evidence suggests that intravenous levetiracetam may be effective as a second-line agent for CSE, and fewer adverse effects have been described. This trial therefore aims to determine whether intravenous phenytoin or levetiracetam is more effective, and safer, in treating childhood CSE.Methods/designThis is a phase IV, multi-centre, parallel group, randomised controlled, open-label trial. Following treatment for CSE with first-line treatment, children with ongoing seizures are randomised to receive either phenytoin (20 mg/kg, maximum 2 g) or levetiracetam (40 mg/kg, maximum 2.5 g) intravenously. The primary outcome measure is the cessation of all visible signs of CSE as determined by the treating clinician. Secondary outcome measures include the need for further anti-seizure medications or rapid sequence induction for ongoing CSE, admission to critical care areas, and serious adverse reactions. Patients are recruited without prior consent, with deferred consent sought at an appropriate time for the family. The primary analysis will be by intention-to-treat. The primary outcome is a time to event outcome and a sample size of 140 participants in each group will have 80% power to detect an increase in CSE cessation rates from 60% to 75%. Our total sample size of 308 randomised and treated participants will allow for 10% loss to follow-up.DiscussionThis clinical trial will determine whether phenytoin or levetiracetam is more effective as an intravenous second-line agent for CSE, and provide evidence for management recommendations. In addition, this trial will also provide data on which of these therapies is safer in this setting.Trial registrationISRCTN identifier, ISRCTN22567894. Registered on 27 August 2015EudraCT identifier, 2014-002188-13. Registered on 21 May 2014NIHR HTA Grant: 12/127/134
Highlights
Convulsive status epilepticus (CSE) is the most common life-threatening neurological emergency in childhood
This clinical trial will determine whether phenytoin or levetiracetam is more effective as an intravenous second-line agent for CSE, and provide evidence for management recommendations
advanced paediatric life support (APLS) recommends phenytoin as the first-choice second-line anticonvulsant; if the child is allergic to phenytoin, has previously not responded to it, or has experienced a serious adverse event (SAE), phenobarbital is recommended
Summary
This study has a number of opportunities and challenges which might affect recruitment. It is an example of paediatric research in an emergency situation and has to involve either waived or deferred consent; waived consent is ethically unacceptable in this setting and research without prior consent will be a new concept to many participating centres. Input and advice was obtained through patient and public involvement and all site training includes a video scenario of a professional mock interview in which the study is discussed and deferred consent is explained, processes designed to maximise recruitment into EcLiPSE. Engagement with PERUKI optimised success through collaboration with clinicians and researchers in the development and delivery of the study, together with the selection of the most appropriate sites in which to recruit patients.
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