Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT.

BACKGROUND: Convulsive status epilepticus is the most common neurological emergency in children. Its management is important to avoid or minimise neurological morbidity and death. The current first-choice second-line drug is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA), for which there is no robust scientific evidence. OBJECTIVE: To determine whether phenytoin or levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) is the more clinically effective intravenous second-line treatment of paediatric convulsive status epilepticus and to help better inform its management. DESIGN: A multicentre parallel-group randomised open-label superiority trial with a nested mixed-method study to assess recruitment and research without prior consent. SETTING: Participants were recruited from 30 paediatric emergency departments in the UK. PARTICIPANTS: Participants aged 6 months to 17 years 11 months, who were presenting with convulsive status epilepticus and were failing to respond to first-line treatment. INTERVENTIONS: Intravenous levetiracetam (40 mg/kg) or intravenous phenytoin (20 mg/kg). MAIN OUTCOME MEASURES: Primary outcome - time from randomisation to cessation of all visible signs of convulsive status epilepticus. Secondary outcomes - further anticonvulsants to manage the convulsive status epilepticus after the initial agent, the need for rapid sequence induction owing to ongoing convulsive status epilepticus, admission to critical care and serious adverse reactions. RESULTS: Between 17 July 2015 and 7 April 2018, 286 participants were randomised, treated and consented. A total of 152 participants were allocated to receive levetiracetam and 134 participants to receive phenytoin. Convulsive status epilepticus was terminated in 106 (70%) participants who were allocated to levetiracetam and 86 (64%) participants who were allocated to phenytoin. Median time from randomisation to convulsive status epilepticus cessation was 35 (interquartile range 20-not assessable) minutes in the levetiracetam group and 45 (interquartile range 24-not assessable) minutes in the phenytoin group (hazard ratio 1.20, 95% confidence interval 0.91 to 1.60; p = 0.2). Results were robust to prespecified sensitivity analyses, including time from treatment commencement to convulsive status epilepticus termination and competing risks. One phenytoin-treated participant experienced serious adverse reactions. LIMITATIONS: First, this was an open-label trial. A blinded design was considered too complex, in part because of the markedly different infusion rates of the two drugs. Second, there was subjectivity in the assessment of 'cessation of all signs of continuous, rhythmic clonic activity' as the primary outcome, rather than fixed time points to assess convulsive status epilepticus termination. However, site training included simulated demonstration of seizure cessation. Third, the time point of randomisation resulted in convulsive status epilepticus termination prior to administration of trial treatment in some cases. This affected both treatment arms equally and had been prespecified at the design stage. Last, safety measures were a secondary outcome, but the trial was not powered to demonstrate difference in serious adverse reactions between treatment groups. CONCLUSIONS: Levetiracetam was not statistically superior to phenytoin in convulsive status epilepticus termination rate, time taken to terminate convulsive status epilepticus or frequency of serious adverse reactions. The results suggest that it may be an alternative to phenytoin in the second-line management of paediatric convulsive status epilepticus. Simple trial design, bespoke site training and effective leadership were found to facilitate practitioner commitment to the trial and its success. We provide a framework to optimise recruitment discussions in paediatric emergency medicine trials. FUTURE WORK: Future work should include a meta-analysis of published studies and the possible sequential use of levetiracetam and phenytoin or sodium valproate in the second-line treatment of paediatric convulsive status epilepticus. TRIAL REGISTRATION: Current Controlled Trials ISRCTN22567894 and European Clinical Trials Database EudraCT number 2014-002188-13. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 58. See the NIHR Journals Library website for further project information.

Most epileptic tonic­clonic seizures, also called convulsions, last for < 4 minutes and stop spontaneously. A convulsion that lasts for > 5 minutes is called convulsive status epilepticus. This may cause neurological abnormalities or, rarely, death. There is good scientific evidence for the best first-line medicine, called a benzodiazepine, to stop convulsive status epilepticus. When a benzodiazepine has not stopped status, a second-line medicine is given. The usual second-line medicine, which has been used for > 50 years, is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA). However, it stops status in only half of children. It must be given slowly because it can cause unpleasant and potentially serious side effects. A new medicine called levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) may be more effective. It seems to have less serious side effects than phenytoin. However, there is no good scientific evidence as to whether phenytoin or levetiracetam is better. A randomised controlled trial is the best scientific way to decide which of these two medicines is better. The Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children (EcLiPSE) trial was a randomised controlled trial that compared levetiracetam with phenytoin. A total of 152 children were randomised to receive levetiracetam and a total of 134 children were randomised to receive phenytoin. Research without prior consent was shown to be acceptable to parents, doctors and nurses. Parents' consent to use their child's data and continue in the trial was provided after the emergency situation was resolved. Convulsive status epilepticus stopped in 70.4% of the levetiracetam-treated children and in 64% of the phenytoin-treated children. The median time to status stopping was 35 minutes in the levetiracetam-treated children and 45 minutes in the phenytoin-treated children. Only one participant on phenytoin (vs. none on levetiracetam) experienced serious side effects that were thought to be caused by their treatment. None of the results showed any statistically significant or meaningful difference between levetiracetam and phenytoin. However, the results suggest that levetiracetam might be an alternative choice to phenytoin.

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

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.

Induction of tumor-specific T-cell responses by vaccination with tumor lysate-loaded dendritic cells in colorectal cancer patients with carcinoembryonic-antigen positive tumors.

BACKGROUND: Dendritic cells (DCs) are the most effective antigen-presenting cells. In the last decade, the use of DCs for immunotherapy of cancer patients has been vastly increased. High endocytic capacity together with a unique capability of initiating primary T-cell responses have made DCs the most potent candidates for this purpose. Although DC vaccination occasionally leads to tumor regression, clinical efficacy, and immunogenicity of DCs in clinical trials has not been yet clarified. The present study evaluated the safety and effectiveness of tumor-lysate loaded DC vaccines in advanced colorectal cancer (CRC) patients with carcinoembryonic antigen (CEA) positive tumors. RESULTS: Six patients HLA-A*0201-positive were vaccinated with autologous DCs loaded with tumor lysates (TL) together with tetanus toxoid antigen, hepatitis B, and influenza matrix peptides. Two additional patients were injected with DCs that were generated from their sibling or parent with one haplotype mismatch. All patients received the vaccines every 2 weeks, with a total of three intra-nodal injections per patient. The results indicated that DC vaccination was safe and well tolerated by the patients. Specific immune responses were detected and in some patients, transient stabilization or even reduction of CEA levels were observed. The injection of haplotype mismatched HLA-A*0201-positive DCs resulted in some enhancement of the anti-tumor response in vitro and led to stabilization/reduction of CEA levels in the serum, compared to the use of autologous DCs. CONCLUSION: Altogether, these results suggest that TL-pulsed DCs may be an effective vaccine method in CRC patients. Elimination of regulatory mechanisms as well as adjustment of the vaccination protocol may improve the efficacy of DC vaccination.

Respiratory symptoms, immunology and organism identification in contaminated metalworking fluid workers. What you see is not what you get.

BACKGROUND: Metal working fluids (MWF) constitute a significant respiratory hazard, although symptoms experienced by workers are often poorly investigated and attributed. AIMS: A single possible case of extrinsic allergic alveolitis (EAA) led to a formal workplace investigation. It was clear that other exposed workers were affected. The aim of this study was to accurately quantify the clinical, immunological and microbiological findings in MWF workers following presentation of a sentinel case. METHODS: Eleven of 21 individuals participated; eight were assessed by symptom questionnaire, spirometry and serology and three workers provided blood samples only. The microbes cultured from MWF and air samples were used to determine the presence of precipitating antibodies. RESULTS: Work-related respiratory symptoms were reported in six of eight individuals questioned, two of these complaining of 'flu-like' symptoms. Personal breathing zone measures identified 2.1 x 10(3) to 1.1 x 10(5) colony-forming units/m3 air (CFU/m3). Pseudomonas fluorescens was isolated from air samples. Despite visible 'fungal' contamination of MWF, airborne fungi were detectable in only one sample, at 486 CFU/m3 air. MWF cultured Eurotium sp., Fusarium sp. and Pseudomonas sp. Precipitating IgG antibodies to Pseudomonas sp. were identified in 4/11 and to an extract of the MWF in 3/11. IgG to Pseudomonas was elevated in the two individuals who had the strongest precipitating bands to Pseudomonas sp. CONCLUSIONS: Workplaces with possible EAA must be investigated promptly, thus allowing clinical assessment to be contemporary to exposures and accurate microbiological profiling included to identify the likely cause.