Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial | Epilepsy and Seizures | JAMA Neurology | JAMA Network
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1.
Wirrell  EC, Laux  L, Donner  E,  et al.  Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American consensus panel.  Pediatr Neurol. 2017;68:18-34.e3. doi:10.1016/j.pediatrneurol.2017.01.025PubMedGoogle ScholarCrossref
2.
Wu  YW, Sullivan  J, McDaniel  SS,  et al.  Incidence of Dravet syndrome in a US population.  Pediatrics. 2015;136(5):e1310-e1315. doi:10.1542/peds.2015-1807PubMedGoogle ScholarCrossref
3.
Dravet  C, Bureau  M, Oguni  H, Fukuyama  Y, Cokar  O.  Severe myoclonic epilepsy in infancy: Dravet syndrome.  Adv Neurol. 2005;95:71-102.PubMedGoogle Scholar
4.
Depienne  C, Trouillard  O, Saint-Martin  C,  et al.  Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients.  J Med Genet. 2009;46(3):183-191. doi:10.1136/jmg.2008.062323PubMedGoogle ScholarCrossref
5.
Skluzacek  JV, Watts  KP, Parsy  O, Wical  B, Camfield  P.  Dravet syndrome and parent associations: the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief.  Epilepsia. 2011;52(suppl 2):95-101. doi:10.1111/j.1528-1167.2011.03012.xPubMedGoogle ScholarCrossref
6.
Cooper  MS, Mcintosh  A, Crompton  DE,  et al.  Mortality in Dravet syndrome.  Epilepsy Res. 2016;128:43-47. doi:10.1016/j.eplepsyres.2016.10.006PubMedGoogle ScholarCrossref
7.
Harden  C, Tomson  T, Gloss  D,  et al.  Practice guideline summary: sudden unexpected death in epilepsy incidence rates and risk factors: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology and the American Epilepsy Society.  Epilepsy Curr. 2017;17(3):180-187. doi:10.5698/1535-7511.17.3.180PubMedGoogle ScholarCrossref
8.
Aras  LM, Isla  J, Mingorance-Le Meur  A.  The European patient with Dravet syndrome: results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome.  Epilepsy Behav. 2015;44:104-109. doi:10.1016/j.yebeh.2014.12.028PubMedGoogle ScholarCrossref
9.
De Liso  P, Chemaly  N, Laschet  J,  et al.  Patients with Dravet syndrome in the era of stiripentol: a French cohort cross-sectional study.  Epilepsy Res. 2016;125:42-46. doi:10.1016/j.eplepsyres.2016.05.012PubMedGoogle ScholarCrossref
10.
Harden  C, Tomson  T, Gloss  D,  et al.  Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society.  Neurology. 2017;88(17):1674-1680. doi:10.1212/WNL.0000000000003685PubMedGoogle ScholarCrossref
11.
Chiron  C, Helias  M, Kaminska  A,  et al.  Do children with Dravet syndrome continue to benefit from stiripentol for long through adulthood?  Epilepsia. 2018;59(9):1705-1717. doi:10.1111/epi.14536PubMedGoogle ScholarCrossref
12.
Lagae  L, Sullivan  J, Helen Cross  J,  et al.  ZX008 (fenfluramine HCl oral solution) in Dravet syndrome: results of a phase 3, randomized, double-blind, placebo-controlled trial.  Lancet. in press.Google Scholar
13.
Rubino  C, Boyd  B, Zhang  L, Ismail  M, Trang  M, Farfel  GM. ZX008 (fenfluramine oral solution) as adjunctive therapy for Dravet syndrome seizures: a pharmacometric approach to quantify potential drug-drug interactions to support phase 3 dose selection. Annual Meeting of the America Epilepsy Society; December 1-5, 2017; Washington, DC.
14.
U.S. Department of Health and Human Services Food and Drug Administration. Center for Drug Evaluation and Research; Center for Biologics Evaluation and Research. E6(R2) Good clinical practice: integrated addendum to ICH E6(R1) guidance for industry. https://www.fda.gov/media/93884/download. Published March 2018. Accessed October 28, 2019.
15.
Boyd  B, Smith  S, Gammaitoni  A, Galer  BS, Farfel  GM.  A phase I, randomized, open-label, single-dose, 3-period crossover study to evaluate the drug-drug interaction between ZX008 (fenfluramine HCl oral solution) and a regimen of stiripentol, clobazam, and valproate in healthy subjects.  Int J Clin Pharmacol Ther. 2019;57(1):11-19. doi:10.5414/CP203276PubMedGoogle ScholarCrossref
16.
Sabaz  M, Lawson  JA, Cairns  DR,  et al.  Validation of the quality of life in childhood epilepsy questionnaire in American epilepsy patients.  Epilepsy Behav. 2003;4(6):680-691. doi:10.1016/j.yebeh.2003.08.012PubMedGoogle ScholarCrossref
17.
Varni  JW, Seid  M, Kurtin  PS.  PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations.  Med Care. 2001;39(8):800-812. doi:10.1097/00005650-200108000-00006PubMedGoogle ScholarCrossref
18.
Ziobro  J, Eschbach  K, Sullivan  JE, Knupp  KG.  Current treatment strategies and future treatment options for Dravet syndrome.  Curr Treat Options Neurol. 2018;20(12):52. doi:10.1007/s11940-018-0537-yPubMedGoogle ScholarCrossref
19.
Chiron  C.  Stiripentol for the treatment of Dravet syndrome.  Orphan Drugs Res Rev. 2014;4:29-38. doi:10.2147/ODRR.S47619Google ScholarCrossref
20.
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):1638-1642. doi:10.1016/S0140-6736(00)03157-3PubMedGoogle ScholarCrossref
21.
European Medicines Agency. Diacomit: EPAR—scientific discussion. https://www.ema.europa.eu/en/documents/scientific-discussion/diacomit-epar-scientific-discussion_en.pdf. Published January 29, 2009. Accessed February 28, 2019.
22.
Devinsky  O, Cross  JH, Laux  L,  et al; Cannabidiol in Dravet Syndrome Study Group.  Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome.  N Engl J Med. 2017;376(21):2011-2020. doi:10.1056/NEJMoa1611618PubMedGoogle ScholarCrossref
23.
Webb  RH, Gentles  TL, Stirling  JW, Lee  M, O’Donnell  C, Wilson  NJ.  Valvular regurgitation using portable echocardiography in a healthy student population: implications for rheumatic heart disease screening.  J Am Soc Echocardiogr. 2015;28(8):981-988. doi:10.1016/j.echo.2015.03.012PubMedGoogle ScholarCrossref
24.
Bachorik  L. FDA announces withdrawal fenfluramine and dexfenfluramine (Fen-Phen). https://wayback.archive-it.org/7993/20170723090512/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm179871.htm. Published 1997. Accessed May 29, 2018.
25.
Abenhaim  L, Moride  Y, Brenot  F,  et al; International Primary Pulmonary Hypertension Study Group.  Appetite-suppressant drugs and the risk of primary pulmonary hypertension.  N Engl J Med. 1996;335(9):609-616. doi:10.1056/NEJM199608293350901PubMedGoogle ScholarCrossref
26.
Dahl  CF, Allen  MR, Urie  PM, Hopkins  PN.  Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals.  BMC Med. 2008;6:34. doi:10.1186/1741-7015-6-34PubMedGoogle ScholarCrossref
27.
Hopkins  PN, Polukoff  GI.  Risk of valvular heart disease associated with use of fenfluramine.  BMC Cardiovasc Disord. 2003;3:5. doi:10.1186/1471-2261-3-5PubMedGoogle ScholarCrossref
28.
Jick  H, Vasilakis  C, Weinrauch  LA, Meier  CR, Jick  SS, Derby  LE.  A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation.  N Engl J Med. 1998;339(11):719-724. doi:10.1056/NEJM199809103391102PubMedGoogle ScholarCrossref
29.
Rich  S, Rubin  L, Walker  AM, Schneeweiss  S, Abenhaim  L.  Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension.  Chest. 2000;117(3):870-874. doi:10.1378/chest.117.3.870PubMedGoogle ScholarCrossref
30.
Schoonjans  A, Paelinck  BP, Marchau  F,  et al.  Low-dose fenfluramine significantly reduces seizure frequency in Dravet syndrome: a prospective study of a new cohort of patients.  Eur J Neurol. 2017;24(2):309-314. doi:10.1111/ene.13195PubMedGoogle ScholarCrossref
31.
Lai  WW, Pringsheim  M, Farfel  G,  et al. Long-term cardiovascular safety of Fintepla® (fenfluramine HCl oral solution) in the treatment of Dravet syndrome: interim analysis of an open-label safety extension study [poster]. American Epilepsy Society (AES) Annual Meeting; November 30–December 4, 2018; New Orleans, LA.
32.
Schoonjans  AS, Marchau  F, Paelinck  BP,  et al.  Cardiovascular safety of low-dose fenfluramine in Dravet syndrome: a review of its benefit-risk profile in a new patient population.  Curr Med Res Opin. 2017;33(10):1773-1781. doi:10.1080/03007995.2017.1355781PubMedGoogle ScholarCrossref
33.
Ceulemans  B, Boel  M, Leyssens  K,  et al.  Successful use of fenfluramine as an add-on treatment for Dravet syndrome.  Epilepsia. 2012;53(7):1131-1139. doi:10.1111/j.1528-1167.2012.03495.xPubMedGoogle ScholarCrossref
34.
Ceulemans  B, Schoonjans  AS, Marchau  F, Paelinck  BP, Lagae  L.  Five-year extended follow-up status of 10 patients with Dravet syndrome treated with fenfluramine.  Epilepsia. 2016;57(7):e129-e134. doi:10.1111/epi.13407PubMedGoogle ScholarCrossref
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    Original Investigation
    December 2, 2019

    Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial

    Author Affiliations
    • 1Hôpital Universitaire Necker–Enfants Malades, Service de Neurologie Pédiatrique Centre de Référence Épilepsies Rares, Imagine Institute, Institut National de la Santé et de la Recherche Médicale, Unite Mixté de Recherche 1163, Paris Descartes University, Paris, France
    • 2Zogenix, Inc, Emeryville, California
    • 3Paediatric Neurosciences Research Group, Royal Hospital for Children Glasgow, Glasgow, United Kingdom
    • 4Assistance Publique–Hôpitaux de Marseille, Department of Pediatric Neurology, Hôpital de la Timone, Marseille, France
    • 5Hospital Ruber Internacional, Madrid, Spain
    • 6Pediatric Neurology Unit, Clínica Universidad de Navarra, Pamplona, Spain
    • 7Department of Neuropediatrics, Christian-Albrechts-University, Kiel, Germany
    • 8Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois
    • 9Mayo Clinic, Rochester, Minnesota
    • 10University of Colorado, Children’s Hospital Colorado, Aurora
    • 11Pediatric Neurology, Necker-Enfants Malades Hospital, Institut National de la Santé et de la Recherche Médicale Unite 1141, Paris, France
    • 12Robert Debré University Hospital, Université de Paris, Institut National de la Santé et de la Recherche Médicale Unite 1141, Paris, France
    JAMA Neurol. 2020;77(3):300-308. doi:10.1001/jamaneurol.2019.4113
    Key Points

    Question  Is fenfluramine safe and effective for treating patients with Dravet syndrome who have frequent seizures despite taking a stiripentol-inclusive antiepileptic drug regimen?

    Findings  Oral fenfluramine (0.4 mg/kg/d; maximum 17 mg/d) provided a 54.0% greater reduction in mean monthly convulsive seizure frequency than placebo in patients with Dravet syndrome who were taking stiripentol-containing antiepileptic drug regimens; a significantly greater proportion of patients who were taking fenfluramine (vs placebo) experienced a clinically meaningful (≥50%) or profound (≥75%) reduction in monthly convulsive seizure frequency. The most common adverse events included decreased appetite, pyrexia, fatigue, and diarrhea; no patient developed valvular heart disease or pulmonary hypertension.

    Meaning  Adjunctive fenfluramine may be a safe, effective new treatment option for patients with Dravet syndrome with seizures that are not controlled by a regimen including stiripentol.

    Abstract

    Importance  Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens.

    Objective  To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens.

    Design, Setting, and Participants  This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens.

    Interventions  Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary.

    Main Outcomes and Measures  The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline.

    Results  A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (≥50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension.

    Conclusions and Relevance  Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome.

    Trial Registration  ClinicalTrials.gov identifier: NCT02926898

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