{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T23:04:18Z","timestamp":1782255858985,"version":"3.54.5"},"reference-count":28,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2018,8,26]],"date-time":"2018-08-26T00:00:00Z","timestamp":1535241600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100012739","name":"Zogenix","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012739","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Lennox\u2010Gastaut syndrome (<jats:styled-content style=\"fixed-case\">LGS<\/jats:styled-content>) is a drug\u2010resistant, childhood onset electroclinical epilepsy syndrome with multiple seizure types and diagnostic electroencephalogram findings. <jats:styled-content style=\"fixed-case\">ZX<\/jats:styled-content>008 (fenfluramine <jats:styled-content style=\"fixed-case\">HC<\/jats:styled-content>l oral solution) was well tolerated and reduced seizure frequency in Dravet syndrome, prompting this phase 2, open\u2010label, dose\u2010finding study of add\u2010on <jats:styled-content style=\"fixed-case\">ZX<\/jats:styled-content>008 in patients with <jats:styled-content style=\"fixed-case\">LGS<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>02655198).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eligible treatment\u2010refractory patients with <jats:styled-content style=\"fixed-case\">LGS<\/jats:styled-content> aged 3\u201018 years with \u22654 documented convulsive seizures (<jats:styled-content style=\"fixed-case\">CS<\/jats:styled-content>) in the prior 4 weeks were administered adjunctive <jats:styled-content style=\"fixed-case\">ZX<\/jats:styled-content>008 twice daily at an initial dose of 0.2 mg\/kg\/d, with incremental dose escalations up to 0.8 mg\/kg\/d or 30 mg\/d (maximum dose) every 4 weeks in nonresponders (&lt;50% reduction in <jats:styled-content style=\"fixed-case\">CS<\/jats:styled-content> frequency). After 20 weeks (core study), responders were offered entry into a long\u2010term extension study. Seizures were captured via diary. Cardiac safety was monitored by Doppler echocardiography and electrocardiogram.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirteen patients were enrolled (mean age = 11.7 years, range = 3\u201017). Ten (77%) patients completed 20 weeks of <jats:styled-content style=\"fixed-case\">ZX<\/jats:styled-content>008 treatment. During the core study, there was a 53% median reduction (N = 13) in <jats:styled-content style=\"fixed-case\">CS<\/jats:styled-content>; median reduction was 60% in the 10 completers. Eight patients (62%) had a \u226550% <jats:styled-content style=\"fixed-case\">CS<\/jats:styled-content> reduction; three (23%) patients had a \u226575% reduction. Nine (69%) patients entered the long\u2010term extension study. At 15 months (n = 9), median reduction in <jats:styled-content style=\"fixed-case\">CS<\/jats:styled-content> was 58%; six (67%) patients had a \u226550% reduction, and three (33%) patients had a \u226575% reduction. The most common adverse events were decreased appetite (n = 4, 31%) and decreased alertness (n = 2, 15%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">ZX<\/jats:styled-content>008 provided clinically meaningful reduction (\u226550%) in <jats:styled-content style=\"fixed-case\">CS<\/jats:styled-content> frequency in the majority of patients with <jats:styled-content style=\"fixed-case\">LGS<\/jats:styled-content> in this pilot study and was generally well tolerated. A phase 3, randomized, controlled study is ongoing.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.14540","type":"journal-article","created":{"date-parts":[[2018,8,28]],"date-time":"2018-08-28T05:26:09Z","timestamp":1535433969000},"page":"1881-1888","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["A pilot, open\u2010label study of the effectiveness and tolerability of low\u2010dose <scp>ZX<\/scp>008 (fenfluramine <scp>HC<\/scp>l) in Lennox\u2010Gastaut syndrome"],"prefix":"10.1111","volume":"59","author":[{"given":"Lieven","family":"Lagae","sequence":"first","affiliation":[{"name":"Department of Development and Regeneration Division of Pediatric Neurology University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An\u2010Sofie","family":"Schoonjans","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Antwerp University Hospital University of Antwerp Edegem Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnold R.","family":"Gammaitoni","sequence":"additional","affiliation":[{"name":"Zogenix Emeryville California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley S.","family":"Galer","sequence":"additional","affiliation":[{"name":"Zogenix Emeryville California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berten","family":"Ceulemans","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Antwerp University Hospital University of Antwerp Edegem Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,8,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(08)70292-8"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2017.00505"},{"key":"e_1_2_9_4_1","first-page":"CD003277","article-title":"Treatment of Lennox\u2010Gastaut syndrome","author":"Hancock EC","year":"2013","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073817714394"},{"key":"e_1_2_9_6_1","unstructured":"National Institute for Health and Care Excellence.Epilepsies: diagnosis and management;2018. Available at:https:\/\/www.nice.org.uk\/guidance\/cg137. Accessed May 3 2018."},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.2147\/NDT.S1668"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.13195"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13407"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2012.03495.x"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/1756285615607726"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/03007995.2017.1355781"},{"key":"e_1_2_9_13_1","unstructured":"LagaeL SullivanJ Helen CrossJ et al.ZX008 (fenfluramine HCl oral solution) in Dravet syndrome: results of a phase 3 randomized double\u2010blind placebo\u2010controlled trial [abstract]. Presented at: 71st Annual Meeting of the American Epilepsy Society; December 1\u20105 2017; Washington DC."},{"key":"e_1_2_9_14_1","unstructured":"MartinP MauriceM GammaitoniA FarfelG BoydB GalerB.Fenfluramine has in vivo activity as a positive modulator of sigma\u20101 receptors [abstract]. Presented at: 71st Annual Meeting of the American Epilepsy Society; December 1\u20105 2017;Washington DC."},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0091-3057(88)90089-5"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00191"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.081101"},{"key":"e_1_2_9_18_1","unstructured":"European Medicines Agency.Guideline on clinical investigation of medicinal products in the treatment of epileptic disorders 2010. Available at:http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2010\/01\/WC500070043.pdf. Accessed May 3 2018."},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13709"},{"key":"e_1_2_9_20_1","unstructured":"International League Against Epilepsy.EpilepsyDiagnosis.org;2018. Available at:https:\/\/www.epilepsydiagnosis.org\/. Accessed May 16 2018."},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2011.03177.x"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-017-3188-y"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30136-3"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1714631"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01487068"},{"key":"e_1_2_9_26_1","article-title":"A phase I, randomized, open\u2010label, single\u2010dose, 3\u2010period crossover study to evaluate the drug\u2010drug interaction between ZX008 (fenfluramine HCl oral solution) and a regimen of stiripentol, clobazam, and valproate in healthy volunteers","author":"Boyd B","journal-title":"Int J Clin Pharmacol Ther"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.105.007237"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(97)90044-8"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004714-199808000-00015"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fepi.14540","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.14540","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T00:16:11Z","timestamp":1694736971000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.14540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,26]]},"references-count":28,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2018,10]]}},"alternative-id":["10.1111\/epi.14540"],"URL":"https:\/\/doi.org\/10.1111\/epi.14540","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,26]]},"assertion":[{"value":"2018-06-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-07-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}