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Open Access 09-05-2024 | Dravet Syndrome | ORIGINAL RESEARCH

Additional Results from Two Randomized, Placebo-Controlled Trials of Stiripentol in Dravet Syndrome Highlight a Rapid Antiseizure Efficacy with Longer Seizure-Free Periods

Authors: Renzo Guerrini, Laurent Chancharme, Benjamin Serraz, Catherine Chiron

Published in: Neurology and Therapy | Issue 3/2024

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Abstract

Introduction

The efficacy of stiripentol in Dravet syndrome children was evidenced in two randomized, double-blind, placebo-controlled, phase 3 studies, namely STICLO France (October 1996–August 1998) and STICLO Italy (April 1999–October 2000), but data were not fully exploited at the time.

Methods

This post-hoc analysis used additional information, notably collected during the open-label extension (OLE) month, or reported by caregivers in individual diaries, to evaluate new outcomes.

Results

Overall, 64 patients were included (31 in the placebo group, 33 in the stiripentol group) of whom 34 (53.1%) were female. Patients’ mean and median (25%; 75%) age were 9.2 years (range 3.0–20.7 years) and 8.7 years (6.0; 12.1) respectively. At the end of the double-blind treatment period, 72% of the patients in the stiripentol group had a ≥ 50% decrease in generalized tonic–clonic seizure (GTCS) frequency, versus 7% in the placebo group (P < 0.001), 56% had a profound (≥ 75%) decrease versus 3% in the placebo group (P < 0.001), and 38% were free of GTCS, but none in the placebo group (P < 0.001). The onset of stiripentol efficacy was rapid, significant from the fourth day of treatment onwards. The median longest period of consecutive days with no GTCS was 32 days in the stiripentol group compared to 8.5 days in the placebo group (P < 0.001). Further to the switch to the third month OLE, an 80.2% decrease in seizure frequency from baseline was observed in patients previously receiving placebo, while no change in efficacy was observed in those already on stiripentol. Adverse events were more frequent in the stiripentol group, with significantly more episodes of somnolence, anorexia, and weight decrease than in the placebo group.

Conclusion

Altogether these new analyses of the STICLO data reinforce the evidence for a remarkable efficacy of stiripentol in Dravet syndrome, with a demonstrated rapid onset of action and sustained response, as also evidenced in further post-randomized trials.
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Literature
1.
go back to reference Dravet C. Severe epilepsy in children. La Vie Médicale. 1978;8(2):543–8. Dravet C. Severe epilepsy in children. La Vie Médicale. 1978;8(2):543–8.
3.
4.
go back to reference Sullivan J, Deighton AM, Vila MC, Szabo SM, Maru B, Gofshteyn JS, et al. The clinical, economic, and humanistic burden of Dravet syndrome—a systematic literature review. Epilepsy Behav. 2022;130: 108661.CrossRefPubMed Sullivan J, Deighton AM, Vila MC, Szabo SM, Maru B, Gofshteyn JS, et al. The clinical, economic, and humanistic burden of Dravet syndrome—a systematic literature review. Epilepsy Behav. 2022;130: 108661.CrossRefPubMed
5.
go back to reference Wirrell EC, Hood V, Knupp KG, Meskis MA, Nabbout R, Scheffer IE, et al. International consensus on diagnosis and management of Dravet syndrome. Epilepsia. 2022;63(7):1761–77.CrossRefPubMedPubMedCentral Wirrell EC, Hood V, Knupp KG, Meskis MA, Nabbout R, Scheffer IE, et al. International consensus on diagnosis and management of Dravet syndrome. Epilepsia. 2022;63(7):1761–77.CrossRefPubMedPubMedCentral
6.
go back to reference Strzelczyk A, Lagae L, Wilmshurst J, Brunklaus A, Striano P, Rosenow F, et al. Dravet syndrome: a systematic literature review of the illness burden. Epilepsia Open. 2023;8:1256–70.CrossRefPubMedPubMedCentral Strzelczyk A, Lagae L, Wilmshurst J, Brunklaus A, Striano P, Rosenow F, et al. Dravet syndrome: a systematic literature review of the illness burden. Epilepsia Open. 2023;8:1256–70.CrossRefPubMedPubMedCentral
7.
8.
go back to reference Perez J, Chiron C, Musial C, Rey E, Blehaut H, d’Athis P, et al. Stiripentol: efficacy and tolerability in children with epilepsy. Epilepsia. 1999;40(11):1618–26.CrossRefPubMed Perez J, Chiron C, Musial C, Rey E, Blehaut H, d’Athis P, et al. Stiripentol: efficacy and tolerability in children with epilepsy. Epilepsia. 1999;40(11):1618–26.CrossRefPubMed
9.
go back to reference Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia. 1998;39(5):508–12.CrossRefPubMed Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia. 1998;39(5):508–12.CrossRefPubMed
10.
go back to reference Guerrini R, Tonnelier S, d’Athis P, Rey P, Vincent J, Pons G, et al. Stiripentol in severe myoclonic epilepsy in infancy (SMEI): a placebo-controlled italian trial. Epilepsia. 2002;43(Suppl. 8):155. Guerrini R, Tonnelier S, d’Athis P, Rey P, Vincent J, Pons G, et al. Stiripentol in severe myoclonic epilepsy in infancy (SMEI): a placebo-controlled italian trial. Epilepsia. 2002;43(Suppl. 8):155.
11.
go back to reference Chiron C, Marchand MC, Tran A, Rey E, d’Athis P, Vincent J, 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.CrossRefPubMed Chiron C, Marchand MC, Tran A, Rey E, d’Athis P, Vincent J, 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.CrossRefPubMed
12.
go back to reference de Liso P, Chemaly N, Laschet J, Barnerias C, Hully M, Leunen D, et al. Patients with Dravet syndrome in the era of stiripentol: a French cohort cross-sectional study. Epilepsy Res. 2016;125:42–6.CrossRefPubMed de Liso P, Chemaly N, Laschet J, Barnerias C, Hully M, Leunen D, et al. Patients with Dravet syndrome in the era of stiripentol: a French cohort cross-sectional study. Epilepsy Res. 2016;125:42–6.CrossRefPubMed
13.
go back to reference Myers KA, Lightfoot P, Patil SG, Cross JH, Scheffer IE. Stiripentol efficacy and safety in Dravet syndrome: a 12-year observational study. Dev Med Child Neurol. 2018;60(6):574–8.CrossRefPubMed Myers KA, Lightfoot P, Patil SG, Cross JH, Scheffer IE. Stiripentol efficacy and safety in Dravet syndrome: a 12-year observational study. Dev Med Child Neurol. 2018;60(6):574–8.CrossRefPubMed
14.
go back to reference Chiron C, Helias M, Kaminska A, Laroche C, de Toffol B, Dulac O, et al. Do children with Dravet syndrome continue to benefit from stiripentol for long through adulthood? Epilepsia. 2018;59(9):1705–17.CrossRefPubMed Chiron C, Helias M, Kaminska A, Laroche C, de Toffol B, Dulac O, et al. Do children with Dravet syndrome continue to benefit from stiripentol for long through adulthood? Epilepsia. 2018;59(9):1705–17.CrossRefPubMed
15.
go back to reference Chiron C, Chemaly N, Chancharme L, Nabbout R. Initiating stiripentol before 2 years of age in patients with Dravet syndrome is safe and beneficial against status epilepticus. Dev Med Child Neurol. 2023;65(12):1607–16.CrossRefPubMed Chiron C, Chemaly N, Chancharme L, Nabbout R. Initiating stiripentol before 2 years of age in patients with Dravet syndrome is safe and beneficial against status epilepticus. Dev Med Child Neurol. 2023;65(12):1607–16.CrossRefPubMed
16.
go back to reference Biocodex. Periodic benefit-risk evaluation report for the active substance stiripentol. 2022. Biocodex. Periodic benefit-risk evaluation report for the active substance stiripentol. 2022.
17.
go back to reference Dravet C, Bureau M, Guerrini R, Giraud N, Roger J. Severe myoclonic epilepsy in infants. In: Epileptic syndromes in infancy, childhood and adolescence, 2nd ed. Barnet: John Libbey and Company Ltd; 1992. Dravet C, Bureau M, Guerrini R, Giraud N, Roger J. Severe myoclonic epilepsy in infants. In: Epileptic syndromes in infancy, childhood and adolescence, 2nd ed. Barnet: John Libbey and Company Ltd; 1992.
18.
go back to reference Brown LD, Cai T, DasGupta A. Interval estimation for a binomial proportion. Stat Sci. 2001;16(2):101–17.CrossRef Brown LD, Cai T, DasGupta A. Interval estimation for a binomial proportion. Stat Sci. 2001;16(2):101–17.CrossRef
19.
20.
go back to reference Editorial. How best to serve children. Lancet 2000; 356:1619. Editorial. How best to serve children. Lancet 2000; 356:1619.
21.
go back to reference Kassaï B, Chiron C, Augier S, Cucherat M, Rey E, Gueyffier F, et al. Severe myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual patient data. Epilepsia. 2008;49(2):343–8.CrossRefPubMed Kassaï B, Chiron C, Augier S, Cucherat M, Rey E, Gueyffier F, et al. Severe myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual patient data. Epilepsia. 2008;49(2):343–8.CrossRefPubMed
22.
go back to reference Brigo F, Storti M. Antiepileptic drugs for the treatment of severe myoclonic epilepsy in infancy. Cochrane Database Syst Rev. 2013;11:CD010483. Brigo F, Storti M. Antiepileptic drugs for the treatment of severe myoclonic epilepsy in infancy. Cochrane Database Syst Rev. 2013;11:CD010483.
23.
go back to reference Lattanzi S, Trinka E, Russo E, Del Giovane C, Matricardi S, Meletti S, et al. Pharmacotherapy for Dravet syndrome: a systematic review and network meta-analysis of randomized controlled trials. Drugs. 2023;15:1409–24.CrossRef Lattanzi S, Trinka E, Russo E, Del Giovane C, Matricardi S, Meletti S, et al. Pharmacotherapy for Dravet syndrome: a systematic review and network meta-analysis of randomized controlled trials. Drugs. 2023;15:1409–24.CrossRef
24.
go back to reference Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011–20.CrossRefPubMed Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011–20.CrossRefPubMed
25.
go back to reference Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019;394:2243–54.CrossRefPubMed Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019;394:2243–54.CrossRefPubMed
26.
go back to reference Bishop KI, Isquith PK, Gioia GA, Gammaitoni AR, Farfel G, Galer BS, et al. Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome. Epilepsy Behav. 2021;121(Pt A): 108024.CrossRefPubMed Bishop KI, Isquith PK, Gioia GA, Gammaitoni AR, Farfel G, Galer BS, et al. Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome. Epilepsy Behav. 2021;121(Pt A): 108024.CrossRefPubMed
27.
go back to reference Shmuely S, Sisodiya SM, Gunning WB, Sander JW, Thijs RD. Mortality in Dravet syndrome: a review. Epilepsy Behav. 2016;64:69–74.CrossRefPubMed Shmuely S, Sisodiya SM, Gunning WB, Sander JW, Thijs RD. Mortality in Dravet syndrome: a review. Epilepsy Behav. 2016;64:69–74.CrossRefPubMed
28.
go back to reference Auvin S, Damera V, Martin M, Holland R, Simontacchi K, Saich A. The impact of seizure frequency on quality of life in patients with Lennox-Gastaut syndrome or Dravet syndrome. Epilepsy Behav. 2021;123: 108239.CrossRefPubMed Auvin S, Damera V, Martin M, Holland R, Simontacchi K, Saich A. The impact of seizure frequency on quality of life in patients with Lennox-Gastaut syndrome or Dravet syndrome. Epilepsy Behav. 2021;123: 108239.CrossRefPubMed
29.
go back to reference Lo SH, Lloyd A, Marshall J, Vyas K. Patient and caregiver health state utilities in Lennox-Gastaut syndrome and Dravet syndrome. Clin Ther. 2021;43(11):1861–76.CrossRefPubMed Lo SH, Lloyd A, Marshall J, Vyas K. Patient and caregiver health state utilities in Lennox-Gastaut syndrome and Dravet syndrome. Clin Ther. 2021;43(11):1861–76.CrossRefPubMed
30.
go back to reference Pinsent A, Weston G, Adams EJ, Linley W, Hawkins N, Schwenkglenks M, et al. Determining the relationship between seizure-free days and other predictors of quality of life in patients with Dravet syndrome and their carers from FFA registration studies. Neurol Ther. 2023;12(5):1593–606.CrossRefPubMedPubMedCentral Pinsent A, Weston G, Adams EJ, Linley W, Hawkins N, Schwenkglenks M, et al. Determining the relationship between seizure-free days and other predictors of quality of life in patients with Dravet syndrome and their carers from FFA registration studies. Neurol Ther. 2023;12(5):1593–606.CrossRefPubMedPubMedCentral
31.
go back to reference Inoue Y, Ohtsuka Y, Oguni H, Tohyama J, Baba H, Fukushima K, et al. Stiripentol open study in Japanese patients with Dravet syndrome. Epilepsia. 2009;50(11):2362–8.CrossRefPubMed Inoue Y, Ohtsuka Y, Oguni H, Tohyama J, Baba H, Fukushima K, et al. Stiripentol open study in Japanese patients with Dravet syndrome. Epilepsia. 2009;50(11):2362–8.CrossRefPubMed
32.
go back to reference Inoue Y, Ohtsuka Y. Long-term safety and efficacy of stiripentol for the treatment of Dravet syndrome: a multicenter, open-label study in Japan. Epilepsy Res. 2015;113:90–7.CrossRefPubMed Inoue Y, Ohtsuka Y. Long-term safety and efficacy of stiripentol for the treatment of Dravet syndrome: a multicenter, open-label study in Japan. Epilepsy Res. 2015;113:90–7.CrossRefPubMed
33.
go back to reference Wirrell EC, Laux L, Franz DN, Sullivan J, Saneto RP, Morse RP, et al. Stiripentol in Dravet syndrome: results of a retrospective U.S. study. Epilepsia. 2013;54(9):1595–604.CrossRefPubMed Wirrell EC, Laux L, Franz DN, Sullivan J, Saneto RP, Morse RP, et al. Stiripentol in Dravet syndrome: results of a retrospective U.S. study. Epilepsia. 2013;54(9):1595–604.CrossRefPubMed
34.
go back to reference Balestrini S, Doccini V, Boncristiano A, Lenge M, De Masi S, Guerrini R. Efficacy and safety of long-term treatment with stiripentol in children and adults with drug-resistant epilepsies: a retrospective cohort study of 196 patients. Drugs Real World Outcomes. 2022;9(3):451–61.CrossRefPubMedPubMedCentral Balestrini S, Doccini V, Boncristiano A, Lenge M, De Masi S, Guerrini R. Efficacy and safety of long-term treatment with stiripentol in children and adults with drug-resistant epilepsies: a retrospective cohort study of 196 patients. Drugs Real World Outcomes. 2022;9(3):451–61.CrossRefPubMedPubMedCentral
35.
go back to reference Thanh TN, Chiron C, Dellatolas G, Rey E, Pons G, Vincent J, et al. Long-term efficacy and tolerance of stiripentol in severe myoclonic epilepsy of infancy (Dravet’s syndrome. Arch Pediatr. 2002;9(11):1120–7.PubMed Thanh TN, Chiron C, Dellatolas G, Rey E, Pons G, Vincent J, et al. Long-term efficacy and tolerance of stiripentol in severe myoclonic epilepsy of infancy (Dravet’s syndrome. Arch Pediatr. 2002;9(11):1120–7.PubMed
36.
go back to reference Yamada M, Suzuki K, Matsui D, Inoue Y, Ohtsuka Y. Long-term safety and effectiveness of stiripentol in patients with Dravet syndrome: interim report of a post-marketing surveillance study in Japan. Epilepsy Res. 2020;170: 106535.CrossRefPubMed Yamada M, Suzuki K, Matsui D, Inoue Y, Ohtsuka Y. Long-term safety and effectiveness of stiripentol in patients with Dravet syndrome: interim report of a post-marketing surveillance study in Japan. Epilepsy Res. 2020;170: 106535.CrossRefPubMed
Metadata
Title
Additional Results from Two Randomized, Placebo-Controlled Trials of Stiripentol in Dravet Syndrome Highlight a Rapid Antiseizure Efficacy with Longer Seizure-Free Periods
Authors
Renzo Guerrini
Laurent Chancharme
Benjamin Serraz
Catherine Chiron
Publication date
09-05-2024
Publisher
Springer Healthcare
Keyword
Dravet Syndrome
Published in
Neurology and Therapy / Issue 3/2024
Print ISSN: 2193-8253
Electronic ISSN: 2193-6536
DOI
https://doi.org/10.1007/s40120-024-00623-8

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