Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial
IMPORTANCE: Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC). OBJECTIVE: To evaluate efficacy and safety of...
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| Veröffentlicht in: | JAMA neurology 2021-03, Vol.78 (3), p.285-292 |
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| creator | Thiele, Elizabeth A Bebin, E. Martina Bhathal, Hari Jansen, Floor E Kotulska, Katarzyna Lawson, John A O'Callaghan, Finbar J Wong, Michael Sahebkar, Farhad Checketts, Daniel Knappertz, Volker |
| description | IMPORTANCE: Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC). OBJECTIVE: To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication. INTERVENTIONS: Patients received oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period. RESULTS: Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P |
| doi_str_mv | 10.1001/jamaneurol.2020.4607 |
| format | Article |
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Martina ; Bhathal, Hari ; Jansen, Floor E ; Kotulska, Katarzyna ; Lawson, John A ; O'Callaghan, Finbar J ; Wong, Michael ; Sahebkar, Farhad ; Checketts, Daniel ; Knappertz, Volker</creator><creatorcontrib>Thiele, Elizabeth A ; Bebin, E. Martina ; Bhathal, Hari ; Jansen, Floor E ; Kotulska, Katarzyna ; Lawson, John A ; O'Callaghan, Finbar J ; Wong, Michael ; Sahebkar, Farhad ; Checketts, Daniel ; Knappertz, Volker ; GWPCARE6 Study Group</creatorcontrib><description>IMPORTANCE: Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC). OBJECTIVE: To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication. INTERVENTIONS: Patients received oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period. RESULTS: Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo. CONCLUSIONS AND RELEVANCE: Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02544763</description><identifier>ISSN: 2168-6149</identifier><identifier>EISSN: 2168-6157</identifier><identifier>DOI: 10.1001/jamaneurol.2020.4607</identifier><identifier>PMID: 33346789</identifier><language>eng</language><publisher>United States: American Medical Association</publisher><subject>Adolescent ; Adult ; Anticonvulsants - administration & dosage ; Anticonvulsants - adverse effects ; Cannabidiol - administration & dosage ; Cannabidiol - adverse effects ; Child ; Child, Preschool ; Comments ; Diarrhea - chemically induced ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Infant ; Internationality ; Male ; Middle Aged ; Online First ; Original Investigation ; Seizures - diagnosis ; Seizures - drug therapy ; Seizures - epidemiology ; Sleepiness - drug effects ; Treatment Outcome ; Tuberous Sclerosis - diagnosis ; Tuberous Sclerosis - drug therapy ; Tuberous Sclerosis - epidemiology ; Young Adult</subject><ispartof>JAMA neurology, 2021-03, Vol.78 (3), p.285-292</ispartof><rights>Copyright 2020 Thiele EA et al. .</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a330t-285be061b70777d3645810d7c1878ac04d94a39cb6a533dd29999b2590433d383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jamanetwork.com/journals/jamaneurology/articlepdf/10.1001/jamaneurol.2020.4607$$EPDF$$P50$$Gama$$H</linktopdf><linktohtml>$$Uhttps://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2020.4607$$EHTML$$P50$$Gama$$H</linktohtml><link.rule.ids>64,230,314,777,781,882,3327,27905,27906,76238,76241</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33346789$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thiele, Elizabeth A</creatorcontrib><creatorcontrib>Bebin, E. Martina</creatorcontrib><creatorcontrib>Bhathal, Hari</creatorcontrib><creatorcontrib>Jansen, Floor E</creatorcontrib><creatorcontrib>Kotulska, Katarzyna</creatorcontrib><creatorcontrib>Lawson, John A</creatorcontrib><creatorcontrib>O'Callaghan, Finbar J</creatorcontrib><creatorcontrib>Wong, Michael</creatorcontrib><creatorcontrib>Sahebkar, Farhad</creatorcontrib><creatorcontrib>Checketts, Daniel</creatorcontrib><creatorcontrib>Knappertz, Volker</creatorcontrib><creatorcontrib>GWPCARE6 Study Group</creatorcontrib><title>Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial</title><title>JAMA neurology</title><addtitle>JAMA Neurol</addtitle><description>IMPORTANCE: Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC). OBJECTIVE: To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication. INTERVENTIONS: Patients received oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period. RESULTS: Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo. CONCLUSIONS AND RELEVANCE: Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02544763</description><subject>Adolescent</subject><subject>Adult</subject><subject>Anticonvulsants - administration & dosage</subject><subject>Anticonvulsants - adverse effects</subject><subject>Cannabidiol - administration & dosage</subject><subject>Cannabidiol - adverse effects</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Comments</subject><subject>Diarrhea - chemically induced</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Humans</subject><subject>Infant</subject><subject>Internationality</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Online First</subject><subject>Original Investigation</subject><subject>Seizures - diagnosis</subject><subject>Seizures - drug therapy</subject><subject>Seizures - epidemiology</subject><subject>Sleepiness - drug effects</subject><subject>Treatment Outcome</subject><subject>Tuberous Sclerosis - diagnosis</subject><subject>Tuberous Sclerosis - drug therapy</subject><subject>Tuberous Sclerosis - epidemiology</subject><subject>Young Adult</subject><issn>2168-6149</issn><issn>2168-6157</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUdtu1DAQtRCIVqU_gBDyIy_Z-pY44QFpFS5FqgRql2drEnuLK8de7ARBP4DvZlZbFpgXjzznzOUcQl5wtuKM8Ys7mCC6JaewEkywlWqYfkROBW_aquG1fnzMVXdCzku5YxgtY0qqp-RESqka3Xan5Nfa2ipF2kOMMHjrU6Cb7GCeXJzpNmX6Ni-31bUrvsyAXzfO3y_ZFeoj3SyDy2kp9GYMmCCE9mnaBffjNV3TzwFGN6SqT3HGRYOz9BqiTZO_x7QPPvoR9tM8hGfkyRZCcecP7xn58v7dpr-srj59-NivryqQks2VaOvBsYYPmmmtrWxU3XJm9chb3cLIlO0UyG4cGqiltFZ0GIOoO7xbWtnKM_Lm0He3DJOzIx6ZIZhd9hPknyaBN_9Xov9qbtN3o3WtUD9s8OqhQU7fFldmM_kyuhDQDlTCCKU5jhaiQag6QEeUpmS3PY7hzOxdNH9dNHsXzd5FpL38d8Uj6Y9nCHh-ACD7WBVaK8mV_A1iZ6WW</recordid><startdate>20210301</startdate><enddate>20210301</enddate><creator>Thiele, Elizabeth A</creator><creator>Bebin, E. Martina</creator><creator>Bhathal, Hari</creator><creator>Jansen, Floor E</creator><creator>Kotulska, Katarzyna</creator><creator>Lawson, John A</creator><creator>O'Callaghan, Finbar J</creator><creator>Wong, Michael</creator><creator>Sahebkar, Farhad</creator><creator>Checketts, Daniel</creator><creator>Knappertz, Volker</creator><general>American Medical Association</general><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20210301</creationdate><title>Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial</title><author>Thiele, Elizabeth A ; Bebin, E. Martina ; Bhathal, Hari ; Jansen, Floor E ; Kotulska, Katarzyna ; Lawson, John A ; O'Callaghan, Finbar J ; Wong, Michael ; Sahebkar, Farhad ; Checketts, Daniel ; Knappertz, Volker</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a330t-285be061b70777d3645810d7c1878ac04d94a39cb6a533dd29999b2590433d383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Anticonvulsants - administration & dosage</topic><topic>Anticonvulsants - adverse effects</topic><topic>Cannabidiol - administration & dosage</topic><topic>Cannabidiol - adverse effects</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Comments</topic><topic>Diarrhea - chemically induced</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Humans</topic><topic>Infant</topic><topic>Internationality</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Online First</topic><topic>Original Investigation</topic><topic>Seizures - diagnosis</topic><topic>Seizures - drug therapy</topic><topic>Seizures - epidemiology</topic><topic>Sleepiness - drug effects</topic><topic>Treatment Outcome</topic><topic>Tuberous Sclerosis - diagnosis</topic><topic>Tuberous Sclerosis - drug therapy</topic><topic>Tuberous Sclerosis - epidemiology</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thiele, Elizabeth A</creatorcontrib><creatorcontrib>Bebin, E. 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Martina</au><au>Bhathal, Hari</au><au>Jansen, Floor E</au><au>Kotulska, Katarzyna</au><au>Lawson, John A</au><au>O'Callaghan, Finbar J</au><au>Wong, Michael</au><au>Sahebkar, Farhad</au><au>Checketts, Daniel</au><au>Knappertz, Volker</au><aucorp>GWPCARE6 Study Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial</atitle><jtitle>JAMA neurology</jtitle><addtitle>JAMA Neurol</addtitle><date>2021-03-01</date><risdate>2021</risdate><volume>78</volume><issue>3</issue><spage>285</spage><epage>292</epage><pages>285-292</pages><issn>2168-6149</issn><eissn>2168-6157</eissn><abstract>IMPORTANCE: Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC). OBJECTIVE: To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication. INTERVENTIONS: Patients received oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period. RESULTS: Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo. CONCLUSIONS AND RELEVANCE: Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02544763</abstract><cop>United States</cop><pub>American Medical Association</pub><pmid>33346789</pmid><doi>10.1001/jamaneurol.2020.4607</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; American Medical Association Journals |
| subjects | Adolescent Adult Anticonvulsants - administration & dosage Anticonvulsants - adverse effects Cannabidiol - administration & dosage Cannabidiol - adverse effects Child Child, Preschool Comments Diarrhea - chemically induced Dose-Response Relationship, Drug Double-Blind Method Female Follow-Up Studies Humans Infant Internationality Male Middle Aged Online First Original Investigation Seizures - diagnosis Seizures - drug therapy Seizures - epidemiology Sleepiness - drug effects Treatment Outcome Tuberous Sclerosis - diagnosis Tuberous Sclerosis - drug therapy Tuberous Sclerosis - epidemiology Young Adult |
| title | Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial |
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