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Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6
Objective To estimate the timing of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]) onset, we conducted a post hoc analysis of GWPCARE6 (NCT02544763), a randomized, placebo‐controlled, phase 3 trial in patients with drug‐resistant epilepsy associated with tuberous scl...
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| Published in: | Epilepsia (Copenhagen) 2022-05, Vol.63 (5), p.1189-1199 |
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| container_title | Epilepsia (Copenhagen) |
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| creator | Wu, Joyce Y. Cock, Hannah R. Devinsky, Orrin Joshi, Charuta Miller, Ian Roberts, Colin M. Sanchez‐Carpintero, Rocio Checketts, Daniel Sahebkar, Farhad |
| description | Objective
To estimate the timing of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]) onset, we conducted a post hoc analysis of GWPCARE6 (NCT02544763), a randomized, placebo‐controlled, phase 3 trial in patients with drug‐resistant epilepsy associated with tuberous sclerosis complex (TSC).
Methods
Patients received plant‐derived pharmaceutical formulation of highly purified CBD (Epidiolex; 100 mg/ml oral solution) at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or placebo for 16 weeks (4‐week titration, 12‐week maintenance). Treatment started at 5 mg/kg/day for all groups and reached 25 mg/kg/day on Day 9 and 50 mg/kg/day on Day 29. Percentage change from baseline in TSC‐associated seizure (countable focal or generalized) count was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.
Results
Of 224 patients, 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo. Median (range) age was 11.3 (1.1–56.8) years. Patients had discontinued a median (range) of 4 (0–15) antiseizure medications and were currently taking 3 (0–5). Difference in seizure reduction between CBD and placebo emerged on Day 6 (titrated dose, 15 mg/kg/day) and became nominally significant (p |
| doi_str_mv | 10.1111/epi.17199 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9314914</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2629852187</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4439-eff15816705da7297e8b0c91af34c5acd5113a4f7026a33fad614d5ad9a629813</originalsourceid><addsrcrecordid>eNp1ktFqFDEUhgdR7Fq98AUk4I1ebJtMJjMTLwplWWuhYJGKl-Fs5oybkpmsSWZ1fSlf0bNuLSqYmwTOx5c_J6congt-Imid4sadiEZo_aCYCVW2cyHq5mEx41zIuVYtPyqepHTLOW_qRj4ujqQSjarLclb8uHEDshxYGBNmFnpmYRxh5ToXPMsRIQ84ZoZ9jzYzGDsWMQU_ZRfGPQ7dFmNChlvCEnMjy9MKY5gSS9bTIbnEbBg2Hr-9YdchZbYOlkTgd_sSKSJZw-C-Y0fgmGPwno6bNZBWUgYHnl18ul6cf1jWT4tHPfiEz-724-Lj2-XN4t386v3F5eL8am6rSuo5xRWqpS5w1UFT6gbbFbdaQC8rq8B2SggJVd_wsgYpe-hqUXUKOg11qVshj4uzg3czrQbsLD0ugjeb6AaIOxPAmb8ro1ubz2FrtBSVFhUJXt0JYvgyYcpmcMmi9zAiNceU-3tUKdqG0Jf_oLdhitSgPaW0Vo1WNVGvD5SlnqaI_X0Ywc1-DAyNgfk1BsS--DP9Pfn73wk4PQBfncfd_01meX15UP4Ee6fABQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2659957956</pqid></control><display><type>article</type><title>Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6</title><source>Wiley</source><creator>Wu, Joyce Y. ; Cock, Hannah R. ; Devinsky, Orrin ; Joshi, Charuta ; Miller, Ian ; Roberts, Colin M. ; Sanchez‐Carpintero, Rocio ; Checketts, Daniel ; Sahebkar, Farhad</creator><creatorcontrib>Wu, Joyce Y. ; Cock, Hannah R. ; Devinsky, Orrin ; Joshi, Charuta ; Miller, Ian ; Roberts, Colin M. ; Sanchez‐Carpintero, Rocio ; Checketts, Daniel ; Sahebkar, Farhad</creatorcontrib><description>Objective
To estimate the timing of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]) onset, we conducted a post hoc analysis of GWPCARE6 (NCT02544763), a randomized, placebo‐controlled, phase 3 trial in patients with drug‐resistant epilepsy associated with tuberous sclerosis complex (TSC).
Methods
Patients received plant‐derived pharmaceutical formulation of highly purified CBD (Epidiolex; 100 mg/ml oral solution) at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or placebo for 16 weeks (4‐week titration, 12‐week maintenance). Treatment started at 5 mg/kg/day for all groups and reached 25 mg/kg/day on Day 9 and 50 mg/kg/day on Day 29. Percentage change from baseline in TSC‐associated seizure (countable focal or generalized) count was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.
Results
Of 224 patients, 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo. Median (range) age was 11.3 (1.1–56.8) years. Patients had discontinued a median (range) of 4 (0–15) antiseizure medications and were currently taking 3 (0–5). Difference in seizure reduction between CBD and placebo emerged on Day 6 (titrated dose, 15 mg/kg/day) and became nominally significant (p < .049) by Day 10. Separation between placebo and CBD in ≥50% responder rate also emerged by Day 10. Onset of AEs occurred during the first 2 weeks of the titration period in 61% of patients (CBD25, 61%; CBD50, 67%; placebo, 54%). In patients with an AE, resolution occurred within 4 weeks of onset in 42% of placebo and 27% of CBD patients and by end of trial in 78% of placebo and 51% of CBD patients.
Significance
Onset of treatment effect occurred within 6–10 days. AEs lasted longer for CBD than placebo, but the most common (diarrhea, decreased appetite, and somnolence) resolved during the 16‐week trial in most patients.</description><identifier>ISSN: 0013-9580</identifier><identifier>EISSN: 1528-1167</identifier><identifier>DOI: 10.1111/epi.17199</identifier><identifier>PMID: 35175622</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Adolescent ; Adult ; Anticonvulsants - adverse effects ; antiseizure medication ; Appetite loss ; Cannabidiol ; Cannabidiol - adverse effects ; Cannabinoids ; Child ; Convulsions & seizures ; Diarrhea ; Double-Blind Method ; Epilepsy ; focal seizures ; Humans ; medication‐resistant seizures ; Middle Aged ; Patients ; Placebos ; Seizures ; Seizures - chemically induced ; Seizures - etiology ; Titration ; Treatment Outcome ; Tuberous sclerosis ; Tuberous Sclerosis - complications ; Tuberous Sclerosis - drug therapy ; tuberous sclerosis complex ; Young Adult</subject><ispartof>Epilepsia (Copenhagen), 2022-05, Vol.63 (5), p.1189-1199</ispartof><rights>2022 The Authors. published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.</rights><rights>2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.</rights><rights>2022. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4439-eff15816705da7297e8b0c91af34c5acd5113a4f7026a33fad614d5ad9a629813</citedby><cites>FETCH-LOGICAL-c4439-eff15816705da7297e8b0c91af34c5acd5113a4f7026a33fad614d5ad9a629813</cites><orcidid>0000-0003-3502-788X ; 0000-0003-0416-1015 ; 0000-0002-5656-0141 ; 0000-0003-0044-4632 ; 0000-0003-4502-7242 ; 0000-0002-5058-0686</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35175622$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Joyce Y.</creatorcontrib><creatorcontrib>Cock, Hannah R.</creatorcontrib><creatorcontrib>Devinsky, Orrin</creatorcontrib><creatorcontrib>Joshi, Charuta</creatorcontrib><creatorcontrib>Miller, Ian</creatorcontrib><creatorcontrib>Roberts, Colin M.</creatorcontrib><creatorcontrib>Sanchez‐Carpintero, Rocio</creatorcontrib><creatorcontrib>Checketts, Daniel</creatorcontrib><creatorcontrib>Sahebkar, Farhad</creatorcontrib><title>Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6</title><title>Epilepsia (Copenhagen)</title><addtitle>Epilepsia</addtitle><description>Objective
To estimate the timing of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]) onset, we conducted a post hoc analysis of GWPCARE6 (NCT02544763), a randomized, placebo‐controlled, phase 3 trial in patients with drug‐resistant epilepsy associated with tuberous sclerosis complex (TSC).
Methods
Patients received plant‐derived pharmaceutical formulation of highly purified CBD (Epidiolex; 100 mg/ml oral solution) at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or placebo for 16 weeks (4‐week titration, 12‐week maintenance). Treatment started at 5 mg/kg/day for all groups and reached 25 mg/kg/day on Day 9 and 50 mg/kg/day on Day 29. Percentage change from baseline in TSC‐associated seizure (countable focal or generalized) count was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.
Results
Of 224 patients, 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo. Median (range) age was 11.3 (1.1–56.8) years. Patients had discontinued a median (range) of 4 (0–15) antiseizure medications and were currently taking 3 (0–5). Difference in seizure reduction between CBD and placebo emerged on Day 6 (titrated dose, 15 mg/kg/day) and became nominally significant (p < .049) by Day 10. Separation between placebo and CBD in ≥50% responder rate also emerged by Day 10. Onset of AEs occurred during the first 2 weeks of the titration period in 61% of patients (CBD25, 61%; CBD50, 67%; placebo, 54%). In patients with an AE, resolution occurred within 4 weeks of onset in 42% of placebo and 27% of CBD patients and by end of trial in 78% of placebo and 51% of CBD patients.
Significance
Onset of treatment effect occurred within 6–10 days. AEs lasted longer for CBD than placebo, but the most common (diarrhea, decreased appetite, and somnolence) resolved during the 16‐week trial in most patients.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Anticonvulsants - adverse effects</subject><subject>antiseizure medication</subject><subject>Appetite loss</subject><subject>Cannabidiol</subject><subject>Cannabidiol - adverse effects</subject><subject>Cannabinoids</subject><subject>Child</subject><subject>Convulsions & seizures</subject><subject>Diarrhea</subject><subject>Double-Blind Method</subject><subject>Epilepsy</subject><subject>focal seizures</subject><subject>Humans</subject><subject>medication‐resistant seizures</subject><subject>Middle Aged</subject><subject>Patients</subject><subject>Placebos</subject><subject>Seizures</subject><subject>Seizures - chemically induced</subject><subject>Seizures - etiology</subject><subject>Titration</subject><subject>Treatment Outcome</subject><subject>Tuberous sclerosis</subject><subject>Tuberous Sclerosis - complications</subject><subject>Tuberous Sclerosis - drug therapy</subject><subject>tuberous sclerosis complex</subject><subject>Young Adult</subject><issn>0013-9580</issn><issn>1528-1167</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><recordid>eNp1ktFqFDEUhgdR7Fq98AUk4I1ebJtMJjMTLwplWWuhYJGKl-Fs5oybkpmsSWZ1fSlf0bNuLSqYmwTOx5c_J6congt-Imid4sadiEZo_aCYCVW2cyHq5mEx41zIuVYtPyqepHTLOW_qRj4ujqQSjarLclb8uHEDshxYGBNmFnpmYRxh5ToXPMsRIQ84ZoZ9jzYzGDsWMQU_ZRfGPQ7dFmNChlvCEnMjy9MKY5gSS9bTIbnEbBg2Hr-9YdchZbYOlkTgd_sSKSJZw-C-Y0fgmGPwno6bNZBWUgYHnl18ul6cf1jWT4tHPfiEz-724-Lj2-XN4t386v3F5eL8am6rSuo5xRWqpS5w1UFT6gbbFbdaQC8rq8B2SggJVd_wsgYpe-hqUXUKOg11qVshj4uzg3czrQbsLD0ugjeb6AaIOxPAmb8ro1ubz2FrtBSVFhUJXt0JYvgyYcpmcMmi9zAiNceU-3tUKdqG0Jf_oLdhitSgPaW0Vo1WNVGvD5SlnqaI_X0Ywc1-DAyNgfk1BsS--DP9Pfn73wk4PQBfncfd_01meX15UP4Ee6fABQ</recordid><startdate>202205</startdate><enddate>202205</enddate><creator>Wu, Joyce Y.</creator><creator>Cock, Hannah R.</creator><creator>Devinsky, Orrin</creator><creator>Joshi, Charuta</creator><creator>Miller, Ian</creator><creator>Roberts, Colin M.</creator><creator>Sanchez‐Carpintero, Rocio</creator><creator>Checketts, Daniel</creator><creator>Sahebkar, Farhad</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3502-788X</orcidid><orcidid>https://orcid.org/0000-0003-0416-1015</orcidid><orcidid>https://orcid.org/0000-0002-5656-0141</orcidid><orcidid>https://orcid.org/0000-0003-0044-4632</orcidid><orcidid>https://orcid.org/0000-0003-4502-7242</orcidid><orcidid>https://orcid.org/0000-0002-5058-0686</orcidid></search><sort><creationdate>202205</creationdate><title>Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6</title><author>Wu, Joyce Y. ; Cock, Hannah R. ; Devinsky, Orrin ; Joshi, Charuta ; Miller, Ian ; Roberts, Colin M. ; Sanchez‐Carpintero, Rocio ; Checketts, Daniel ; Sahebkar, Farhad</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4439-eff15816705da7297e8b0c91af34c5acd5113a4f7026a33fad614d5ad9a629813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Anticonvulsants - adverse effects</topic><topic>antiseizure medication</topic><topic>Appetite loss</topic><topic>Cannabidiol</topic><topic>Cannabidiol - adverse effects</topic><topic>Cannabinoids</topic><topic>Child</topic><topic>Convulsions & seizures</topic><topic>Diarrhea</topic><topic>Double-Blind Method</topic><topic>Epilepsy</topic><topic>focal seizures</topic><topic>Humans</topic><topic>medication‐resistant seizures</topic><topic>Middle Aged</topic><topic>Patients</topic><topic>Placebos</topic><topic>Seizures</topic><topic>Seizures - chemically induced</topic><topic>Seizures - etiology</topic><topic>Titration</topic><topic>Treatment Outcome</topic><topic>Tuberous sclerosis</topic><topic>Tuberous Sclerosis - complications</topic><topic>Tuberous Sclerosis - drug therapy</topic><topic>tuberous sclerosis complex</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Joyce Y.</creatorcontrib><creatorcontrib>Cock, Hannah R.</creatorcontrib><creatorcontrib>Devinsky, Orrin</creatorcontrib><creatorcontrib>Joshi, Charuta</creatorcontrib><creatorcontrib>Miller, Ian</creatorcontrib><creatorcontrib>Roberts, Colin M.</creatorcontrib><creatorcontrib>Sanchez‐Carpintero, Rocio</creatorcontrib><creatorcontrib>Checketts, Daniel</creatorcontrib><creatorcontrib>Sahebkar, Farhad</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Online Library Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Epilepsia (Copenhagen)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Joyce Y.</au><au>Cock, Hannah R.</au><au>Devinsky, Orrin</au><au>Joshi, Charuta</au><au>Miller, Ian</au><au>Roberts, Colin M.</au><au>Sanchez‐Carpintero, Rocio</au><au>Checketts, Daniel</au><au>Sahebkar, Farhad</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6</atitle><jtitle>Epilepsia (Copenhagen)</jtitle><addtitle>Epilepsia</addtitle><date>2022-05</date><risdate>2022</risdate><volume>63</volume><issue>5</issue><spage>1189</spage><epage>1199</epage><pages>1189-1199</pages><issn>0013-9580</issn><eissn>1528-1167</eissn><abstract>Objective
To estimate the timing of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]) onset, we conducted a post hoc analysis of GWPCARE6 (NCT02544763), a randomized, placebo‐controlled, phase 3 trial in patients with drug‐resistant epilepsy associated with tuberous sclerosis complex (TSC).
Methods
Patients received plant‐derived pharmaceutical formulation of highly purified CBD (Epidiolex; 100 mg/ml oral solution) at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or placebo for 16 weeks (4‐week titration, 12‐week maintenance). Treatment started at 5 mg/kg/day for all groups and reached 25 mg/kg/day on Day 9 and 50 mg/kg/day on Day 29. Percentage change from baseline in TSC‐associated seizure (countable focal or generalized) count was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.
Results
Of 224 patients, 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo. Median (range) age was 11.3 (1.1–56.8) years. Patients had discontinued a median (range) of 4 (0–15) antiseizure medications and were currently taking 3 (0–5). Difference in seizure reduction between CBD and placebo emerged on Day 6 (titrated dose, 15 mg/kg/day) and became nominally significant (p < .049) by Day 10. Separation between placebo and CBD in ≥50% responder rate also emerged by Day 10. Onset of AEs occurred during the first 2 weeks of the titration period in 61% of patients (CBD25, 61%; CBD50, 67%; placebo, 54%). In patients with an AE, resolution occurred within 4 weeks of onset in 42% of placebo and 27% of CBD patients and by end of trial in 78% of placebo and 51% of CBD patients.
Significance
Onset of treatment effect occurred within 6–10 days. AEs lasted longer for CBD than placebo, but the most common (diarrhea, decreased appetite, and somnolence) resolved during the 16‐week trial in most patients.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>35175622</pmid><doi>10.1111/epi.17199</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-3502-788X</orcidid><orcidid>https://orcid.org/0000-0003-0416-1015</orcidid><orcidid>https://orcid.org/0000-0002-5656-0141</orcidid><orcidid>https://orcid.org/0000-0003-0044-4632</orcidid><orcidid>https://orcid.org/0000-0003-4502-7242</orcidid><orcidid>https://orcid.org/0000-0002-5058-0686</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Epilepsia (Copenhagen), 2022-05, Vol.63 (5), p.1189-1199 |
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| subjects | Adolescent Adult Anticonvulsants - adverse effects antiseizure medication Appetite loss Cannabidiol Cannabidiol - adverse effects Cannabinoids Child Convulsions & seizures Diarrhea Double-Blind Method Epilepsy focal seizures Humans medication‐resistant seizures Middle Aged Patients Placebos Seizures Seizures - chemically induced Seizures - etiology Titration Treatment Outcome Tuberous sclerosis Tuberous Sclerosis - complications Tuberous Sclerosis - drug therapy tuberous sclerosis complex Young Adult |
| title | Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6 |
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