{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T06:16:15Z","timestamp":1788243375278,"version":"build-2803163510"},"reference-count":17,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,10,28]],"date-time":"2013-10-28T00:00:00Z","timestamp":1382918400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"UCB Pharma"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>Brivaracetam (<jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content>) is a novel high\u2010affinity synaptic vesicle protein 2<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content> ligand in clinical development for the treatment of epilepsy. This phase <jats:styled-content style=\"fixed-case\">III<\/jats:styled-content> study (<jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>01252; <jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>00490035) evaluated the efficacy and safety\/tolerability of <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> (20, 50, and 100\u00a0mg\/day) compared with placebo (<jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>) in patients aged 16\u201370\u00a0years with uncontrolled focal seizures with\/without secondary generalization, despite treatment with one to two concomitant antiepileptic drugs at a stable and optimal dosage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This was a double\u2010blind, randomized, placebo\u2010controlled trial conducted across <jats:styled-content style=\"fixed-case\">E<\/jats:styled-content>urope and <jats:styled-content style=\"fixed-case\">I<\/jats:styled-content>ndia. Eligible patients had two or more focal seizures\/month for 3\u00a0months prior to screening and eight or more focal seizures during the 8\u2010week prospective baseline. Concomitant use of levetiracetam was limited to 20% of randomized patients. Patients were randomized (1:1:1:1) to <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> 20, 50, 100\u00a0mg\/day or <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content> with no up\u2010titration for 12\u00a0weeks, followed by down\u2010titration or entry into a long\u2010term follow\u2010up study. The primary efficacy end point was percent reduction over <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content> in baseline\u2010adjusted focal seizure frequency\/week over the 12\u2010week treatment period. Comparison of <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> with <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content> was sequential to control for multiplicity (50, 100, 20\u00a0mg\/day), and thus required <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> to demonstrate superiority over <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content> at 50\u00a0mg\/day to meet the primary efficacy end point. Secondary efficacy variables were median percent reduction from baseline in focal seizure frequency\/week, \u226550% responder rate, and seizure freedom (all seizure types). Safety assessments included treatment\u2010emergent adverse events (<jats:styled-content style=\"fixed-case\">TEAE<\/jats:styled-content>s).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Findings<\/jats:title><jats:p>Of 399 randomized patients, 398 were included in the intent\u2010to\u2010treat (<jats:styled-content style=\"fixed-case\">ITT<\/jats:styled-content>) and safety populations. Overall, 367 (92.2%) of 398 patients completed the study (<jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content>: 93.9%, 88.9%, and 94.0% for 20, 50, and 100\u00a0mg\/day, respectively; <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>: 92.0%) and 345 (86.7%) of 398 patients continued into long\u2010term follow\u2010up studies (<jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content>: 87.9%, 82.8%, and 88.0% for 20, 50, and 100\u00a0mg\/day, respectively; <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>: 88.0%). The study did not meet its primary efficacy end point based on the predefined sequential testing strategy. Indeed, percent reduction over <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content> in baseline\u2010adjusted focal seizure frequency\/week (primary efficacy analysis) was 6.8% (p\u00a0=\u00a00.239), 6.5% (p\u00a0=\u00a00.261), and 11.7% (p\u00a0=\u00a00.037) for <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> 20, 50, and 100\u00a0mg\/day, respectively. Median percent reduction from baseline in focal seizure frequency\/week was 30.0% (p\u00a0=\u00a00.019), 26.8% (p\u00a0=\u00a00.092), and 32.5% (p\u00a0=\u00a00.004) for <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> 20, 50, and 100\u00a0mg\/day, respectively, compared with 17.0% for <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>. Responder rates (\u226550%) were 27.3% (p\u00a0=\u00a00.339), 27.3% (p\u00a0=\u00a00.372), and 36.0% (p\u00a0=\u00a00.023) for <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> 20, 50, and 100\u00a0mg\/day, respectively, compared with 20.0% for <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>. Complete seizure freedom was reported by 2\/99, 0\/99, and 4\/100 patients on <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> 20, 50, and 100\u00a0mg\/day, respectively, compared with 0\/100 on <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>. The incidence of <jats:styled-content style=\"fixed-case\">TEAE<\/jats:styled-content>s was higher for <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> 20 (56\/99, 56.6%), 50 (62\/99, 62.6%), and 100\u00a0mg\/day (63\/100, 63.0%) than <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content> (53\/100, 53.0%); most <jats:styled-content style=\"fixed-case\">TEAE<\/jats:styled-content>s were mild or moderate in severity. The most frequently reported <jats:styled-content style=\"fixed-case\">TEAE<\/jats:styled-content>s in the <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> groups were headache, somnolence, dizziness, and fatigue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>In this study of adjunctive <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> (20\u2013100\u00a0mg\/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50\u00a0mg\/day dose was not statistically significant. However, <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> 100\u00a0mg\/day reduced baseline\u2010adjusted focal seizure frequency\/week by 11.7% over <jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>, achieving statistical significance (p\u00a0=\u00a00.037). Secondary efficacy analyses (percent reduction from baseline in focal seizure frequency\/week, \u226550% responder rate) provided supportive evidence for the efficacy of <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> 100\u00a0mg\/day. <jats:styled-content style=\"fixed-case\">BRV<\/jats:styled-content> 20\u2013100\u00a0mg\/day was well tolerated without up\u2010titration, with a high completion rate.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.12432","type":"journal-article","created":{"date-parts":[[2013,10,28]],"date-time":"2013-10-28T14:26:48Z","timestamp":1382970408000},"page":"47-56","source":"Crossref","is-referenced-by-count":208,"title":["Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: Results from a double\u2010blind, randomized, placebo\u2010controlled trial"],"prefix":"10.1111","volume":"55","author":[{"given":"Philippe","family":"Ryvlin","sequence":"first","affiliation":[{"name":"Hospices Civils de Lyon and TIGER CRNL INSERM U1028 CNRS 5292 Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konrad J.","family":"Werhahn","sequence":"additional","affiliation":[{"name":"UCB Pharma Monheim am Rhein Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Blaszczyk","sequence":"additional","affiliation":[{"name":"Collegium Medicum WSEiP Kielce Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin E.","family":"Johnson","sequence":"additional","affiliation":[{"name":"UCB Pharma Raleigh North Carolina U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Lu","sequence":"additional","affiliation":[{"name":"UCB Pharma Raleigh North Carolina U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,10,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.26.15268"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181ec7f7f"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2011.04.064"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2009.10.007"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1981.tb06159.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1989.tb05316.x"},{"key":"e_1_2_7_8_1","unstructured":"JohnsonME LuS MerschhemkeM. 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