CNS Drugs

, Volume 27, Issue 3, pp 185–195 | Cite as

A Revisited Strategy for Antiepileptic Drug Development in Children

Designing an Initial Exploratory Step
  • Catherine Chiron
  • Behrouz Kassai
  • Olivier Dulac
  • Gerard Pons
  • Rima Nabbout
Systematic Review



Randomized controlled trials (RCTs) in refractory paediatric epilepsy usually involve the two main types of epilepsy shared by children and adults, focal epilepsy and Lennox-Gastaut syndrome (LGS). Most other epilepsy syndromes, specifically paediatric, are excluded from drug development. In order to identify among them the candidate(s) for dedicated RCTs with a new drug, the European Medicine Agency (EMA) recently recommended proceeding in two steps: (1) an exploratory (prospective-observational) trial (POT) including a large variety of paediatric epilepsy syndromes and (2) a subsequent RCT in each of those that disclose a signal for possible efficacy.


Our objective was to address the three following issues that have not been addressed by the EMA: (1) to determine a minimal threshold for this signal; (2) to establish a list of epilepsies to evaluate; and (3) to estimate the number of patients to include in such POTs.


We extensively reviewed the POTs (including various syndromes) and RCTs reported in paediatric patients with uncontrolled epilepsy using MEDLINE (from 1990 to 2011) and the Cochrane library. We determined the threshold as the lowest percentage of responders observed in a POT with a positive corresponding RCT. The syndromes that reached this threshold in a POT were those to evaluate in an RCT. The minimal number of patients to include for each syndrome for a POT with a new antiepileptic drug was estimated in order to reach at least this threshold of responders with a 95 % confidence interval.


We found the minimal responder threshold to be 25 %. We identified eight epilepsy types/syndromes reaching this threshold and estimated for each of them the minimal sample needed: refractory focal epilepsy (n = 40), Lennox-Gastaut syndrome (n = 32), infantile spasms (n = 50), Dravet syndrome (n = 32), childhood absence epilepsy (n = 12), other symptomatic generalized epilepsy (n = 38), epileptic encephalopathy with continuous spikes and waves during sleep (n = 7) and epilepsy with myoclonic-astatic seizures (n = 4) [the two last samples may be underestimated due to the lack of RCTs in these conditions].


Among the eight epilepsy types/syndromes that we recommend to systematically include in exploratory trials using the POT procedure, we assume that, for the minimal sample given above, a responder threshold of 25 % will provide a reliable efficacy signal, to be confirmed by a dedicated RCT. This strategy should avoid missing new therapeutic possibilities for children with epilepsy and reduce the off-label use of drugs in paediatric neurology.



We are grateful to Gail Scher who reviewed the manuscript. Dr Chiron has received honoraria from Biocodex, Eisai, Lundbeck, Novartis and Johnson & Johnson, and research support from Biocodex, Eisai, the European Community Sixth and Seventh Framework Thematic Priority Life Sciences, the French Research Agency (ANR), the French Foundation for Research in Epilepsy (FFRE) and the Foundation for Brain Research (FRC). Dr Kassai reports no disclosures. Prof. Dulac has received research support from Biocodex, and the French University. Prof. Pons has received research support from Biocodex, and the French Ministry of Health. Dr Nabbout serves on the scientific advisory board for Novartis and has received research support from Biocodex, Viropharma and the ANR. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. No funding was received to prepare this manuscript.


  1. 1.
    Rheims S, Cucherat M, Arzimanoglou A, et al. Greater response to placebo in children than in adults: a systematic review and meta-analysis in drug-resistant partial epilepsy. PLoS Med. 2008;5(8):e166.PubMedCrossRefGoogle Scholar
  2. 2.
    Bosch X. Pediatric medicine: Europe follows U.S. in testing drugs for children [letter]. Science. 2005;309(5742):1799.PubMedCrossRefGoogle Scholar
  3. 3.
    Chiron C, Dulac O, Pons G. Antiepileptic drug development in children: considerations for a revisited strategy. Drugs. 2008;68(1):17–25.PubMedCrossRefGoogle Scholar
  4. 4.
    Chiron C, Dumas C, Jambaque I, et al. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res. 1997;26(2):389–95.PubMedCrossRefGoogle Scholar
  5. 5.
    Appleton RE, Peters AC, Mumford JP, et al. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia. 1999;40(11):1627–33.PubMedCrossRefGoogle Scholar
  6. 6.
    Elterman RD, Shields WD, Mansfield KA, et al. Randomized trial of vigabatrin in patients with infantile spasms. Neurology. 2001;57(8):1416–21.PubMedCrossRefGoogle Scholar
  7. 7.
    Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet. 2000;356(9242):1638–42.PubMedCrossRefGoogle Scholar
  8. 8.
    Chiron C, Dulac O, Beaumont D, et al. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol 1991;Suppl. 2:S52–S59.Google Scholar
  9. 9.
    Perez J, Chiron C, Musial C, et al. Stiripentol: efficacy and tolerability in children with epilepsy. Epilepsia. 1999;40(11):1618–26.PubMedCrossRefGoogle Scholar
  10. 10.
    Besag FM, Wallace SJ, Dulac O, et al. Lamotrigine for the treatment of epilepsy in childhood. J Pediatr. 1995;127(6):991–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Duchowny M, Pellock JM, Graf WD, et al. A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children: Lamictal Pediatric Partial Seizure Study Group. Neurology. 1999;53(8):1724–31.PubMedCrossRefGoogle Scholar
  12. 12.
    Dulac O, Chiron C, Luna D, et al. Vigabatrin in childhood epilepsy. J Child Neurol 1991;Suppl. 2:S30–S37.Google Scholar
  13. 13.
    Frank LM, Enlow T, Holmes GL, et al. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia. 1999;40(7):973–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Motte J, Trevathan E, Arvidsson JF, et al. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome: Lamictal Lennox-Gastaut Study Group. N Engl J Med. 1997;337(25):1807–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Schlumberger E, Chavez F, Palacios L, et al. Lamotrigine in treatment of 120 children with epilepsy. Epilepsia. 1994;35(2):359–67.PubMedCrossRefGoogle Scholar
  16. 16.
    Chiron C, Dulac O, Gram L. Vigabatrin withdrawal randomized study in children. Epilepsy Res. 1996;25(3):209–15.PubMedCrossRefGoogle Scholar
  17. 17.
    Eriksson AS, Nergardh A, Hoppu K. The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: a randomized, double-blind, crossover study. Epilepsia. 1998;39(5):495–501.PubMedCrossRefGoogle Scholar
  18. 18.
    Farrell K, Connolly MB, Munn R, et al. Prospective, open-label, add-on study of lamotrigine in 56 children with intractable generalized epilepsy. Pediatr Neurol. 1997;16(3):201–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Glauser TA, Ayala R, Elterman RD, et al. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology. 2006;66(11):1654–60.PubMedCrossRefGoogle Scholar
  20. 20.
    Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008;70(21):1950–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Pina-Garza JE, Nordli DR Jr, Rating D, et al. Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures. Epilepsia. 2009;50(5):1141–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Oguni H, Hayashi K, Fukuyama Y. Phase III clinical study of the new antiepileptic drug AD-810, zonisamide, in childhood epilepsy. Jpn J Pediatr. 1988;41:439–50.Google Scholar
  23. 23.
    Chhun S, Troude P, Villeneuve N, et al. A prospective open-labeled trial with levetiracetam in pediatric epilepsy syndromes: continuous spikes and waves during sleep is definitely a target. Seizure. 2011;20(4):320–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Mikaeloff Y, Saint-Martin A, Mancini J, et al. Topiramate: efficacy and tolerability in children according to epilepsy syndromes. Epilepsy Res. 2003;53(3):225–32.PubMedCrossRefGoogle Scholar
  25. 25.
    Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30(4):389–99.Google Scholar
  26. 26.
    Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51(4):676–85.PubMedCrossRefGoogle Scholar
  27. 27.
    Appleton R, Fichtner K, LaMoreaux L, et al. Gabapentin as add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, placebo-controlled study. Gabapentin Paediatric Study Group. Epilepsia. 1999;40(8):1147–54.PubMedCrossRefGoogle Scholar
  28. 28.
    Elterman RD, Glauser TA, Wyllie E, et al. A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children: Topiramate YP Study Group. Neurology. 1999;52(7):1338–44.PubMedCrossRefGoogle Scholar
  29. 29.
    Glauser TA, Nigro M, Sachdeo R, et al. Adjunctive therapy with oxcarbazepine in children with partial seizures: the Oxcarbazepine Pediatric Study Group. Neurology. 2000;54(12):2237–44.PubMedCrossRefGoogle Scholar
  30. 30.
    Uthman BM, Rowan AJ, Ahmann PA, et al. Tiagabine for complex partial seizures: a randomized, add-on, dose-response trial. Arch Neurol. 1998;55(1):56–62.PubMedCrossRefGoogle Scholar
  31. 31.
    Pina-Garza JE, Espinoza R, Nordli DR, et al. Oxcarbazepine adjunctive therapy in infants and young children with partial seizures. Neurology. 2005;65(9):1370–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome): the Felbamate Study Group in Lennox-Gastaut Syndrome. N Engl J Med 1993;328(1):29–33.Google Scholar
  33. 33.
    Sachdeo RC, Glauser TA, Ritter F, et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome: Topiramate YL Study Group. Neurology. 1999;52(9):1882–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Richens A, Chadwick DW, Duncan JS, et al. Adjunctive treatment of partial seizures with tiagabine: a placebo-controlled trial. Epilepsy Res. 1995;21(1):37–42.PubMedCrossRefGoogle Scholar
  35. 35.
    Glauser TA. Preliminary observations on topiramate in pediatric epilepsies. Epilepsia. 1997;38(Suppl. 1):S37–41.PubMedCrossRefGoogle Scholar
  36. 36.
    Tiagabine Shinnar S. Semin Pediatr Neurol. 1997;4(1):24–33.CrossRefGoogle Scholar
  37. 37.
    Avanzini G, Canger R, Dalla BB, et al. Felbamate in therapy-resistant epilepsy: an Italian experience. Felbamate Italian Study Group. Epilepsy Res. 1996;25(3):249–55.PubMedCrossRefGoogle Scholar
  38. 38.
    Grosso S, Franzoni E, Coppola G, et al. Efficacy and safety of levetiracetam: an add-on trial in children with refractory epilepsy. Seizure. 2005;14(4):248–53.PubMedCrossRefGoogle Scholar
  39. 39.
    Uldall P, Bulteau C, Pedersen SA, et al. Tiagabine adjunctive therapy in children with refractory epilepsy: a single-blind dose escalating study. Epilepsy Res. 2000;42(2–3):159–68.PubMedCrossRefGoogle Scholar
  40. 40.
    Yagi K. Overview of Japanese experience-controlled and uncontrolled trials. Seizure. 2004;13(Suppl. 1):S11–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Craig JC, Webster AC, Mitchell A, et al. Expanding the evidence base in transplantation: more and better randomized trials, and extending the value of observational data. Transplantation. 2008;86(1):32–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Klassen TP, Hartling L, Craig JC, et al. Children are not just small adults: the urgent need for high-quality trial evidence in children. PLoS Med. 2008;5(8):e172.PubMedCrossRefGoogle Scholar
  43. 43.
    Chiron C, Tonnelier S, Rey E, et al. Stiripentol in childhood partial epilepsy: randomized placebo-controlled trial with enrichment and withdrawal design. J Child Neurol. 2006;21:496–502.PubMedGoogle Scholar
  44. 44.
    Kassaï B, Chiron C, Augier S, et al. Severe myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual patient data. Epilepsia. 2008;49(2):343–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Catherine Chiron
    • 1
    • 2
    • 3
  • Behrouz Kassai
    • 4
  • Olivier Dulac
    • 1
    • 2
    • 3
  • Gerard Pons
    • 1
    • 2
    • 5
  • Rima Nabbout
    • 1
    • 2
    • 3
  1. 1.Inserm, U663, Service de Neurologie et Metabolisme, Hopital NeckerParisFrance
  2. 2.University Paris DescartesParisFrance
  3. 3.APHP, Department of Pediatric Neurology and MetabolismHospital Necker – Enfants MaladesParisFrance
  4. 4.Department of Clinical PharmacologyEpicime-CIC 201/Inserm-Hospices Civils de Lyon, RIPPS, UMR 5558 CNRS, University Hospital of LyonLyonFrance
  5. 5.APHP, Department of Pediatric Clinical PharmacologyRIPPS, Hospital Cochin – Saint Vincent de PaulParisFrance

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