{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T13:26:04Z","timestamp":1762521964381,"version":"3.37.3"},"reference-count":34,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2016,11,14]],"date-time":"2016-11-14T00:00:00Z","timestamp":1479081600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["113202003"],"award-info":[{"award-number":["113202003"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>In children many antiepileptic drugs (<jats:styled-content style=\"fixed-case\">AED<\/jats:styled-content>s) are prescribed off\u2010label due to a lack of well\u2010designed randomized controlled trials (<jats:styled-content style=\"fixed-case\">RCT<\/jats:styled-content>s). We conducted a multicenter <jats:styled-content style=\"fixed-case\">RCT<\/jats:styled-content> in the Netherlands to compare levetiracetam and valproic acid as monotherapy in children with newly diagnosed epilepsy. After 2 years, we had to stop this investigator\u2010initiated trial prematurely because the inclusion rate was too low. We analyzed the reasons for this failure, assessed the various issues involved in performing <jats:styled-content style=\"fixed-case\">RCT<\/jats:styled-content>s in children, and now give recommendations for future studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A questionnaire was completed by all investigators involved in the study. It included questions about the motivation to participate and the perceived reasons for recruitment failure. We also studied literature about financial, logistic, legal, and ethical aspects of <jats:styled-content style=\"fixed-case\">RCT<\/jats:styled-content>s in children.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Main reasons for recruitment failure were overestimation of the number of eligible <jats:styled-content style=\"fixed-case\">AED<\/jats:styled-content>\u2010naive children referred by general pediatricians; personal preferences of investigators for specific antiepileptic drugs; and the extensive administrative load due to extra regulations and guidelines for children. Fundraising for investigator\u2010initiated trials is difficult and the majority of <jats:styled-content style=\"fixed-case\">RCT<\/jats:styled-content>s concerning <jats:styled-content style=\"fixed-case\">AED<\/jats:styled-content>s are sponsored by pharmaceutical companies. Involving children requires balancing between protection and participation; the randomization procedure and obtaining informed consent are complex for both children and parents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Performing <jats:styled-content style=\"fixed-case\">RCT<\/jats:styled-content>s with <jats:styled-content style=\"fixed-case\">AED<\/jats:styled-content>s in children is important but complicated by logistic, regulatory, legal, and ethical restrictions. Based on our recent experience, our advice to colleagues who are planning a similar trial would be to perform a feasibility pilot study; to set up intensive collaboration with referring pediatricians; to arrange support of a clinical trials unit and a local research nurse during the complete trial period; and to incorporate the possibility of extending the recruitment period. Major investments, both financially from governmental organizations and in time, are imperative for independent <jats:styled-content style=\"fixed-case\">RCT<\/jats:styled-content>s in children.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.12024","type":"journal-article","created":{"date-parts":[[2016,10,15]],"date-time":"2016-10-15T07:46:57Z","timestamp":1476517617000},"page":"32-38","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Investigator\u2010initiated randomized controlled trials in children with epilepsy: Mission impossible?"],"prefix":"10.1002","volume":"2","author":[{"given":"Amerins","family":"Weijenberg","sequence":"first","affiliation":[{"name":"Department of Neurology University Medical Centre Groningen University of Groningen Groningen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra M. C.","family":"Callenbach","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Centre Groningen University of Groningen Groningen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oebele F.","family":"Brouwer","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Centre Groningen University of Groningen Groningen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the LEV\u2010VPA Study Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,11,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2002.t01-1-26901.x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.2165\/00148581-200810040-00003"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)16942-0"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0050172"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12074"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2006.00585.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-015-0248-9"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1999.tb00770.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0902014"},{"key":"e_1_2_8_11_1","doi-asserted-by":"crossref","unstructured":"Strengthening clinical research in children and young people [editorial].LancetMay 23 2015;385. Available at:http:\/\/dx.doi.org\/10.1016\/S0140-6736(15)60974-6. Accessed October 25 2016.","DOI":"10.1016\/S0140-6736(15)60974-6"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2010.07.004"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-1211(97)00025-9"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31826d5ec0"},{"key":"e_1_2_8_15_1","first-page":"1","article-title":"Paediatric regulation L 378","volume":"49","author":"European Parliament","year":"2006","journal-title":"Off J Eur Union"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2011-300286"},{"key":"e_1_2_8_17_1","unstructured":"Priority Medicines for Children.www.priomedchild.eu. Accessed October 31 2016"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)61803-1"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-52891-9.00076-2"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200868010-00002"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2011-301999"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000048200.12663.BC"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2012.03.007"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02670.x"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1177\/08830738040190020901"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2008.07.016"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161210791959854"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2013.03.014"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1067\/mpd.2002.129173"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2009.165902"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0050166"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61818-2"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1067\/mpd.2003.192"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40272-014-0108-y"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2015-310001"}],"container-title":["Epilepsia Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fepi4.12024","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi4.12024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T12:45:55Z","timestamp":1695473155000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/epi4.12024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,14]]},"references-count":34,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2017,3]]}},"alternative-id":["10.1002\/epi4.12024"],"URL":"https:\/\/doi.org\/10.1002\/epi4.12024","archive":["Portico"],"relation":{},"ISSN":["2470-9239","2470-9239"],"issn-type":[{"type":"print","value":"2470-9239"},{"type":"electronic","value":"2470-9239"}],"subject":[],"published":{"date-parts":[[2016,11,14]]},"assertion":[{"value":"2016-10-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-11-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}