{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:25:04Z","timestamp":1792038304646,"version":"4.4.0"},"reference-count":16,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T00:00:00Z","timestamp":1634860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.e., time\u2010to\u2010<jats:italic>n<\/jats:italic>th seizure), using a post hoc time\u2010to\u2010event (TTE) analysis of data from two Phase 3 placebo\u2010controlled trials of adjunctive fenfluramine for DS (Study 1,<jats:italic>N<\/jats:italic>\u00a0=\u00a0119; Study 2,<jats:italic>N<\/jats:italic>\u00a0=\u00a087). Patients aged 2\u201319\u00a0years were randomized to placebo or adjunctive fenfluramine (Study 1: .7\u00a0mg\/kg\/day or .2\u00a0mg\/kg\/day; Study 2: .4\u00a0mg\/kg\/day with stiripentol). Data were analyzed by Kaplan\u2013Meier TTE curves and waterfall plots.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The proportion of patients who never reached baseline seizure frequency was greater with fenfluramine than with placebo (Study 1: fenfluramine .7\u00a0mg\/kg\/day, 60%; fenfluramine .2\u00a0mg\/kg\/day, 31%; placebo, 13%; Study 2: fenfluramine .4\u00a0mg\/kg\/day, 58%; placebo, 2%). Median time\u2010to\u2010<jats:italic>n<\/jats:italic>th seizure was longer after fenfluramine than after placebo (Study 1: fenfluramine .7\u00a0mg\/kg\/day, 13\u00a0weeks; .2\u00a0mg\/kg\/day, 10\u00a0weeks; placebo, 7\u00a0weeks; Study 2: fenfluramine .4\u00a0mg\/kg\/day, 13\u00a0weeks; placebo, 5\u00a0weeks;<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.001). Longest duration of convulsive seizure\u2010free days was increased in active groups versus the placebo group (Study 1: fenfluramine .7 and .2\u00a0mg\/kg\/day, 25.0 and 15.0\u00a0days; placebo, 9.5\u00a0days [<jats:italic>p<\/jats:italic>\u00a0=\u00a0.0001;<jats:italic>p<\/jats:italic>\u00a0=\u00a0.0352]; Study 2: fenfluramine .4\u00a0mg\/kg\/day, 22.0\u00a0days; placebo, 13.0\u00a0days [<jats:italic>p<\/jats:italic>\u00a0=\u00a0.004]). The most common adverse events included decreased appetite, pyrexia, upper respiratory tract infection, diarrhea, and fatigue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>These data demonstrate that fenfluramine can significantly reduce day\u2010to\u2010day seizure burden in patients with DS, providing prolonged periods of convulsive seizure\u2010free days, which may help reduce the physical and emotional disease toll while improving health\u2010related QOL for patients and caregivers.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17106","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T07:43:20Z","timestamp":1634888600000},"page":"130-138","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Fenfluramine significantly reduces day\u2010to\u2010day seizure burden by increasing number of seizure\u2010free days and time between seizures in patients with Dravet syndrome: A time\u2010to\u2010event analysis"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2081-8988","authenticated-orcid":false,"given":"Joseph","family":"Sullivan","sequence":"first","affiliation":[{"name":"University of California, San Francisco San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8120-0287","authenticated-orcid":false,"given":"Nicola","family":"Specchio","sequence":"additional","affiliation":[{"name":"Bambino Ges\u00f9 Children's Hospital Scientific Institute for Research and Health Care (IRCCS) Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0044-4632","authenticated-orcid":false,"given":"Orrin","family":"Devinsky","sequence":"additional","affiliation":[{"name":"New York University Langone Medical Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3874-9749","authenticated-orcid":false,"given":"St\u00e9phane","family":"Auvin","sequence":"additional","affiliation":[{"name":"Robert Debr\u00e9 Children's Hospital Public Hospital Network of Paris (APHP) University of Paris Paris France"},{"name":"University Institute of France (IUF) Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1825-846X","authenticated-orcid":false,"given":"M. Scott","family":"Perry","sequence":"additional","affiliation":[{"name":"Cook Children's Medical Center Fort Worth Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6288-9915","authenticated-orcid":false,"given":"Adam","family":"Strzelczyk","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Gil\u2010Nagel","sequence":"additional","affiliation":[{"name":"Ruber International Hospital Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Dai","sequence":"additional","affiliation":[{"name":"Syneos Health Morrisville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4735-3327","authenticated-orcid":false,"given":"Bradley S.","family":"Galer","sequence":"additional","affiliation":[{"name":"Zogenix Emeryville California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4775-2862","authenticated-orcid":false,"given":"Arnold R.","family":"Gammaitoni","sequence":"additional","affiliation":[{"name":"Zogenix Emeryville California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,10,22]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2011.02994.x"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2017.06.012"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13709"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2016.10.014"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pedhc.2017.12.004"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32500-0"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2019.4113"},{"key":"e_1_2_9_9_1","unstructured":"European Medicines AgencyGuideline on clinical investigation of medicinal products in the treatment of epileptic disorders. 2010.https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010guideline\/guideline\u2010clinical\u2010investigation\u2010medicinal\u2010products\u2010treatment\u2010epileptic\u2010disorders\u2010revision\u20102_en.pdf.Accessed 12 Jun 2019."},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001585"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12239"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.5694\/mja17.00951"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12319"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2017.06.031"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2021.108024"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","unstructured":"AmtmannD SalemR GammaitoniAR GalerBS WilkieD JensenMP.Caregivers\u2019 perspectives on the long\u2010term seizure\u2010 and non\u2010seizure\u2010related benefits of fenfluramine on patients with Dravet syndrome and their families. 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