Title: A pragmatic randomised controlled trial of intravenous levetiracetam versus intravenous phenytoin in terminating acute, prolonged tonic–clonic seizures including convulsive status epilepticus in children, the ‘EcLiPSE’ Study: Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus.
Funder: Department of Health and Social Care

Abstract: Design: National, pragmatic, open label, multi-centre, randomised controlled trial with a three-year recruitment period. Setting: Accident and Emergency Departments (AEDs) in acute hospitals - both Children’s Hospitals and General Hospitals with a separate paediatric AED. Target population: Children of both sexes aged 6 months to 17 years and 11 months (<18th birthday) presenting to the AED requiring treatment to terminate a seizure that has not responded to benzodiazepines as a first line anticonvulsant. Inclusion criteria: 1. Males and females 2. Aged 6 months to less than 17 years and 11 months (<18th birthday) 3. Presenting seizure is tonic-clonic, clonic or focal including convulsive status epilepticus that requires treatment to terminate the seizure Exclusion criteria: 1. Absence, myoclonic or non-convulsive status epilepticus or infantile spasms 2. Pregnancy 3. Known contra-indication including a specific rescue (emergency) care plan that states that the child never responds to phenytoin or to levetiracetam, or a known allergy to either drug 4. Presenting seizure has required previous administration of a second-line antiepileptic drug prior to arrival in the AED Health technologies being assessed: Intravenous levetiracetam infused over 5 minutes at a dose of 40mg/kg, (maximum 2g), or intravenous phenytoin administered over 20 minutes at a dose of 20mg/kg (maximum 1g). The longer infusion time for phenytoin is a consequence of the safety profile of this drug. Measurement of costs and outcomes: Primary outcome: Time to cessation of all visible signs of convulsive seizure activity. Secondary: a) Need for further anticonvulsants to manage the seizure after the initial agent. b) Need for rapid sequence intubation (RSI) with thiopentone or another, similar drug. c) Need to be admitted to intensive care. e) Serious adverse reactions including death, airway complications, and cardiovascular instability (cardiac arrest, arrhythmia and hypotension requiring intervention), extravasation injury (‘purple-glove syndrome’). Sample size: Phenytoin has a reported successful seizure cessation rate of 50-60%. Reported rates of successful seizure cessation for levetiracetam range from 76-100%. When the sample size in each group is 155 participants, with a total number of events of 95, a 0.05 level two-sided log-rank test for equality of survival curves will have 80% power to detect an increase in seizure cessation from 60% to 75%, (a constant hazard ratio of 1.776). A total of 340 participants will allow for a 10% loss to follow up. Statistical plan: The primary analysis will be by 'intention to treat'. A 5% level of statistical significance will be used throughout; all results will be presented with 95% confidence intervals. The primary outcome is a time to event outcome and will be analysed using the log-rank test and Kaplan-Meier curves. Dichotomous outcomes will be analysed using the chi-square test and presented with relative risks. Adjusted analyses will be conducted using logistic regression or Cox Proportional Hazards model as appropriate. Variables to be included in the models will be determined from known prognostic factors. No formal statistical tests will be used to describe and compare randomised groups for baseline characteristics or adverse events. Reasons for missing data will be collected; these should be low, but will be monitored throughout. The trial will be monitored by an independent Data Safety Monitoring Committee who will meet at least annually. The Haybittle-Peto approach will be employed for interim analyses with 99.9% confidence intervals. Decisions around trial continuation will not be based on p-values alone. Consent Study EcLiPSE will involve a mixed method sub study to explore approaches to recruitment and deferred consent. Led by Dr Kerry Woolfall the research will involve parents and EcLiPSE recruiters in interviews, focus groups, questionnaires and recorded trial discussions. Findings will inform how parents are asked to provide consent for their child’s involvement in EcLiPSE. Project timetale (total = 51months): • 9 months to set-up the study. Expressions of interest have already been sought and received from Accident and Emergency Departments (AEDs) through the Medicines for Children Research Network (MCRN) and the North West and North Wales Paediatric Critical Care Medicine network. Screening logs have been, and continue to be completed by all AEDs that have expressed an interest in the study (co-ordinated through the MCRN) • 36 months recruitment • 6 months to analyse and write the Report Expertise in team: The research team members have extensive experience of paediatric epilepsy and emergency medicine. The CI has successfully led a previous HTA-funded study and delivered other RCTs and non-RCTs in epilepsy and in emergency settings relevant to this proposal. The non-clinical members of the team have extensive experience in design, conduct, analysis and reporting of randomised clinical trials in children and in epilepsy and also in the management and supply of medicinal products in compliance with regulations. The trial team includes parents of children with refractory epilepsy and collectively the team has an over-arching passion to introduce a robust evidence-base for the management of paediatric convulsive status epilepticus that aims to reduce the mortality and morbidity associated with this medical emergency.

Lay abstract: Most epileptic seizures and convulsions in children last less than three minutes and will stop spontaneously. However, sometimes the seizure may last longer than three minutes. When this occurs the seizure my continue and may eventually become what is called convulsive status epilepticus (CSE). This is a medical emergency. To prevent CSE from happening children are given an antiepileptic medicine called an emergency or rescue medicine. This is usually given into the cheek cavity, called the buccal cavity, or up the bottom, called the rectum. In many cases this will stop the seizure. However, the seizure will only stop in between four and five out of every 10 children treated with one of these rescue medicines. This means that the seizure will continue in the other five to six children. These children will then be brought to the Accident and Emergency Department (AED) of their local hospital. If the child is still in the seizure they will then be given a different rescue anti-epileptic medicine. This is usually given into a vein, called an intravenous medicine. The first intravenous medicine in the AED they will be given is called lorazepam. This will stop the seizure in about two or three of these five or six children. However, two or three of these five children will not respond to lorazepam. They will be then given another intravenous medicine. For many years the medicine that will then most commonly be given is called phenytoin. This will usually stop the seizure in just over half of the children who receive it. However, it will not stop the seizure in just under half of the children who receive it. In addition, phenytoin has to be given very carefully because it can cause very unpleasant and very serious side-effects that may affect the heart, blood pressure and skin. Some early results of a new anticonvulsant called levetiracetam suggest that this medicine may be more effective and safer than phenytoin. We would like to do some research which might prove these early results. The only scientific way to answer this question is by doing a study called a ‘randomised controlled trial’ (RCT) that will compare intravenous phenytoin with intravenous levetiracetam. The research study will be undertaken in AEDs in Great Britain. The main outcome for the study will be the time taken for the seizure to stop after the medicine is given. Other outcomes will be whether the child needs to be given any additional rescue medicines, whether the child needs to go the intensive care unit, and whether the child develops any unwanted side-effects. The research team is qualified to do this research because it includes all the specialties and skills needed for the study. The team also has a lot of experience in caring for children with seizures and epilepsy and is very active in health research. Some of the research team have children with epilepsy. The costs of the study are justified because the study has to be large, involving many AEDs in the country and undertaken with very careful and strict scientific methods. It is hoped that the results of this RCT will provide new evidence for a more effective and safer treatment of status epilepticus.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL