For personal use only. Not to be reproduced without permission of The Lancet. Summary Background Stiripentol is an inhibitor of cytochrome P450 that showed antiepileptic efficacy in severe myoclonic epilepsy in infancy (SMEI) in association with clobazam and valproate in an open study. To confirm these results, 41 children with SMEI were included in a randomised, placebo- controlled, add-on trial. Methods After a baseline period of 1 month, placebo (n=20) or stiripentol (n=21) was added to valproate and clobazam during a double-blind period of 2 months. Patients then received stiripentol in an open fashion. Responders were defined as having more than 50% reduction in the frequency of clonic (or tonic-clonic) seizures during the second month of the double-blind period compared with baseline. Findings 15 (71%) patients were responders on stiripentol (includingnine free of clonic or tonic-clonic seizures), whereas there was only one (5%) on placebo (none were seizure free; stiripentol 95% CI 52·1–90·7 vs placebo 0–14·6). The 95% CI of the difference was 42·2–85·7. Percentage of change from baseline was higher on stiripentol (⫺69%) than on placebo (+7%), p<0·0001. 21 patients on stiripentol had moderate side-effects (drowsiness, loss of appetite) compared with eight on placebo, but side-effects disappeared when the dose of comedication was decreased in 12 of the 21 cases. Interpretation This controlled trial shows the antiepileptic efficacy, of add-on stiripentol in children with SMEI. The results also provide good reason to focus studies on a specific epilepsy syndrome—a small sample of patients is sufficient to show the efficacy that might have been missed in a heterogeneous population. Lancet 2000; 356: 1638–42 See Commentary page 1623 Introduction Severe childhood epilepsies mostly begin during the first years of life and carry a high risk of mental retardation and learning disorders. Seizures are resistant to conventional antiepileptic drugs and are thought to have a deleteriouseffect on cognitive and motor development. These factors make new antiepileptic compounds attractive for use in severe childhood epilepsies. Most data available for new antiepileptic drugs in children are drawn from open studies. Overall results were disappointing, lacking any evidence of efficacy in this age range for either vigabatrinor lamotrigine. 1,2 Nevertheless, the findings suggested that the response varied according to the type of severe epilepsy. Some types of epilepsy improved, whereas other types worsened, with the risk of not detecting efficacy for the combined population. Later, controlled trials dedicated to specific syndromes showed the efficacy of vigabatrin in infantile spasms, 3,4 and of felbamate, lamotrigine, and topiramate in Lennox-Gastaut syndrome. 5–7 Among severe childhood epilepsies, severe myoclonic epilepsy in infants (SMEI) is one of the most deleterious epilepsy syndromes reported in the syndromic classification of the International League Against Epilepsy. 7 The stereotyped clinical characteristics and the absence of any cerebral lesion make SMEI a nosologically and aetiologically homogeneous syndrome. 8,9 Seizures appear during the first year of life and never come under complete control with conventional antiepileptic drugs. All children develop mental retardation in the second year of life, although development is normal before that time. These patients may be worsened by vigabatrinand lamotrigine. 10,11 Stiripentol is a new antiepileptic compound that inhibits several P450 cytochromes. In an open add-on study combining this drug with clobazam and valproate, ten of the 20 patients with SMEI had over 50% reduction in seizure frequency and three became free of seizures. 12 Patients and methods Patients Patients from 15 French centres entered the protocol with the following criteria of inclusion: 3 years and older; SMEI, defined as onset of the epilepsy in the first year of life with clonic (or tonic-clonic) generalised seizures but normal psychomotordevelopment and normal electroencephalogram (EEG); appearance of myoclonia after 1 year of age; atypical absences; generalised spikes and waves on EEG; mental delay; 8,9 at least four clonic (or tonic-clonic) generalised seizures a month; valproate and clobazam as ongoing antiepileptic drugs. Patients receiving other drugs (except progabide) and those whose parents were unable to comply regularly with drug delivery and daily seizure diary were not included. The design and the conduct of the study were approved by the ethics committee of the coordinating centre. Written informed consent was obtained from the parents or guardian of all patients. ARTICLES 1638 THE LANCET • Vol 356 • November 11, 2000 Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial C Chiron, M C Marchand, A Tran, E Rey, P d’Athis, J Vincent, O Dulac, G Pons, and the STICLO study group* *Members listed at end of paper Departments of Neuropaediatrics and INSERM U 29 (C Chiron MD , O Dulac MD ) and Paediatrics and Perinatal Pharmacology, Hospital Saint Vincent de Paul and University René Descartes, Paris, France (M C Marchand MD , A Tran PhD , E Rey PharmD , G Pons MD ); Biocodex, Montrouge (J Vincent PharmD ); and Biostatistics and Medical Informatics, University Hospital, Dijon (P d’Athis PhD ) Correspondence to: Dr C Chiron, Service de Neuropédiatrie, Hopital Saint Vincent de Paul, 82 avenue Denfert-Rochereau, 75674 Paris cedex 14, France