Levetiracetam Versus Phenytoin for Second-Line Treatment of Pediatric Convulsive Status Epilepticus (EcLiPSE): A Multicentre, Open-Label, Randomized Trial

Lyttle MD, Rainford NEA, Gamble C, Messahel S, Humphreys A, Woolfall K, Roper L, Nablet J, Lee ED, Potter S, Tate P, Iyer A, Evans V, Appleton RE. Lancet. 2019;393:2125-34. doi:10.1016/S0140-6736(19)30724-X.

Background:

Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the United Kingdom; 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 pediatric convulsive status epilepticus.

Methods:

This open-label, randomized clinical trial was undertaken at 30 United Kingdom emergency departments at secondary and tertiary care centers. Participants aged 6 months to less than 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomization schedule to receive levetiracetam (40 mg/kg over 5 minutes) or phenytoin (20 mg/kg over at least 20 minutes), stratified by centre. The primary outcome was time from randomization to cessation of convulsive status epilepticus, analyzed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomization 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 randomized 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 randomization to cessation of convulsive status epilepticus was 35 minutes (interquartile range: 20 to not assessable) in the levetiracetam group and 45 minutes (24 to not assessable) in the phenytoin group (hazard ratio: 1.20, 95% confidence interval: 0·91-1.60; P = .20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral edema 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 pediatric convulsive status epilepticus.

<p> <bold>Levetiracetam Versus Phenytoin for Second-Line Treatment of Convulsive Status Epilepticus in Children (ConSEPT): An Open-Label, Multicentre, Randomized Controlled Trial</bold> </p> <p>Dalziel SR, Borland ML, Furyk J, Bonisch M, Neutze J, Donath S, Francis KL, Sharpe C, Harvey AS, Davidson A, Craig S, Phillips N, George S, Rao A, Cheng N, Zhang M, Kochar A, Brabyn C, Oakley E, Babl FE. <italic>Lancet.</italic> 2019;393:2135-45. doi:<a ext-link-type="uri" href="https://doi.org/10.1016/S0140-6736(19)30722-6">10.1016/S0140-6736(19)30722-6</a>.</p> </sec> <sec> <title>Background:

Phenytoin is the current standard of care for second-line treatment of pediatric convulsive status epilepticus after failure of first-line benzodiazepines, but is only effective in 60% of cases and is associated with considerable adverse effects. A newer anticonvulsant, levetiracetam, can be given more quickly, is potentially more efficacious and has a more tolerable adverse effect profile. We aimed to determine whether phenytoin or levetiracetam is the superior second-line treatment for pediatric convulsive status epilepticus.

Methods:

ConSEPT was an open-label, multicenter, randomized controlled trial conducted in 13 emergency departments in Australia and New Zealand. Children aged between 3 months and 16 years, with convulsive status epilepticus who failed first-line benzodiazepine treatment, were randomly assigned (1:1) using a computer-generated permuted block (block sizes: 2 and 4) randomization sequence, stratified by site and age (≤5 years, >5 years), to receive 20 mg/kg phenytoin (intravenous or intraosseous infusion over 20 minutes) or 40 mg/kg levetiracetam (intravenous or intraosseous infusion over 5 minutes). The primary outcome was clinical cessation of seizure activity 5 minutes after the completion of infusion of the study drug. Analysis was by intention to treat. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12615000129583.

Findings:

Between March 19, 2015, and Nov 29, 2017, 639 children presented to participating emergency departments with convulsive status epilepticus; 127 were missed and 278 did not meet eligibility criteria. The parents of one child declined to give consent, leaving 233 children (114 assigned to phenytoin and 119 assigned to levetiracetam) in the intention-to-treat population. Clinical cessation of seizure activity 5 minutes after completion of infusion of study drug occurred in 68 (60%) patients in the phenytoin group and 60 (50%) patients in the levetiracetam group (risk difference: −9.2% [95% confidence interval: −21.9 to 3.5]; P = .16). One participant in the phenytoin group died at 27 days because of hemorrhagic encephalitis; this death was not thought to be due to the study drug. There were no other serious adverse events.

Interpretation:

Levetiracetam is not superior to phenytoin for second-line management of pediatric convulsive status epilepticus.