{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:42:44Z","timestamp":1792154564126,"version":"4.4.0"},"reference-count":39,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,12,27]],"date-time":"2021-12-27T00:00:00Z","timestamp":1640563200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To evaluate the long\u2010term safety and efficacy of add\u2010on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open\u2010label extension (OLE) of the randomized, placebo\u2010controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Patients who completed the randomized trial enrolled to receive CBD (Epidiolex\n                      <jats:sup>\u00ae<\/jats:sup>\n                      in the United States; Epidyolex\n                      <jats:sup>\u00ae<\/jats:sup>\n                      in the EU; 100\u00a0mg\/mL oral solution). The initial target dose was 25\u00a0mg\/kg\/day, which, based on response and tolerability, could be decreased or increased up to 50\u00a0mg\/kg\/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC\u2010associated (countable focal and generalized) seizures, responder rates, and Subject\/Caregiver Global Impression of Change (S\/CGIC).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13\u00a0years (range, 1\u201357). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One\u2010year retention rate was 79%. Median treatment time was 267\u00a0days (range, 18\u2013910) at a 27\u00a0mg\/kg\/day mean modal dose. Most patients (92%) had an adverse event (AE). Most common AEs were diarrhea (42%), seizure (22%), and decreased appetite (20%). AEs led to permanent discontinuation in 6% of patients. There was one death that was deemed treatment unrelated by the investigator. Elevated liver transaminases occurred in 17 patients (9%) patients; 12 were taking valproate. Median percentage reductions in seizure frequency (12\u2010week windows across 48\u00a0weeks) were 54%\u201368%. Seizure responder rates (\u226550%, \u226575%, 100% reduction) were 53%\u201361%, 29%\u201345%, and 6%\u201311% across 12\u2010week windows for 48\u00a0weeks. Improvement on the S\/CGIC scale was reported by 87% of patients\/caregivers at 26\u00a0weeks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>In patients with TSC, long\u2010term add\u2010on CBD treatment was well tolerated and sustainably reduced seizures through 48\u00a0weeks, with most patients\/caregivers reporting global improvement.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.17150","type":"journal-article","created":{"date-parts":[[2021,12,27]],"date-time":"2021-12-27T04:45:11Z","timestamp":1640580311000},"page":"426-439","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Long\u2010term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open\u2010label extension trial"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3431-4713","authenticated-orcid":false,"given":"Elizabeth A.","family":"Thiele","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1264-3428","authenticated-orcid":false,"given":"E. Martina","family":"Bebin","sequence":"additional","affiliation":[{"name":"University of Alabama School of Medicine Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Filloux","sequence":"additional","affiliation":[{"name":"University of Utah School of Medicine Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7310-276X","authenticated-orcid":false,"given":"Patrick","family":"Kwan","sequence":"additional","affiliation":[{"name":"Monash University and the University of Melbourne Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Loftus","sequence":"additional","affiliation":[{"name":"GW Research Ltd Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farhad","family":"Sahebkar","sequence":"additional","affiliation":[{"name":"Greenwich Biosciences, Inc. Carlsbad California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Sparagana","sequence":"additional","affiliation":[{"name":"Scottish Rite for Children and the University of Texas Southwestern Medical Center Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4735-3431","authenticated-orcid":false,"given":"James","family":"Wheless","sequence":"additional","affiliation":[{"name":"Le Bonheur Children's Hospital and the University of Tennessee Health Science Center Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,27]]},"reference":[{"issue":"49","key":"e_1_2_9_2_1","first-page":"243","article-title":"Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference","volume":"2013","author":"Northrup H","year":"2012","journal-title":"Pediatr Neurol"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61279-9"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra055323"},{"key":"e_1_2_9_5_1","first-page":"2021","article-title":"Optimal management of seizures associated with tuberous sclerosis complex: current and emerging options","volume":"10","author":"Wang S","year":"2014","journal-title":"Neuropsychiatr Dis Treat"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/63.12.1236"},{"key":"e_1_2_9_7_1","unstructured":"Tuberous Sclerosis Complex Alliance.Diagnosis surveillance and management for healthcare professionals.https:\/\/www.tscalliance.org\/healthcare\u2010professionals\/diagnosis\/Accessed September 21 2021."},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1991.tb37754.x"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-016-0553-5"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13467"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31637"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0901-8"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2009.02474.x"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2018.05.006"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0887-8994(01)00312-5"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2008.04.001"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2010.03.003"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2009.08.018"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.13352"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1611618"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000005254"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1714631"},{"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":"10.1111\/epi.13499"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2020.4607"},{"key":"e_1_2_9_26_1","volume-title":"EPIDIOLEX\u00ae (cannabidiol) oral solution [prescribing information]"},{"key":"e_1_2_9_27_1","volume-title":"Epidyolex (cannabidiol) oral solution [summary of product characteristics]"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14670"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14628"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2020.0073"},{"key":"e_1_2_9_31_1","unstructured":"Madan CohenJ CheckettsD DunayevichE GunningB HyslopA MadhavanD et al.Time to onset of cannabidiol (CBD) treatment effect and resolution of adverse events in patients with Dravet syndrome: pooled analysis of 2 randomized controlled trials. 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