Long‐term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open‐label extension trial
Objective To evaluate the long‐term safety and efficacy of add‐on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open‐label extension (OLE) of the randomized, placebo‐controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February...
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| Published in | Epilepsia (Copenhagen) Vol. 63; no. 2; pp. 426 - 439 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Wiley Subscription Services, Inc
01.02.2022
John Wiley and Sons Inc |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Objective
To evaluate the long‐term safety and efficacy of add‐on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open‐label extension (OLE) of the randomized, placebo‐controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.
Methods
Patients who completed the randomized trial enrolled to receive CBD (Epidiolex® in the United States; Epidyolex® in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC‐associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC).
Results
Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1–57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One‐year retention rate was 79%. Median treatment time was 267 days (range, 18–910) at a 27 mg/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‐week windows across 48 weeks) were 54%–68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%–61%, 29%–45%, and 6%–11% across 12‐week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks.
Significance
In patients with TSC, long‐term add‐on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement. |
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| AbstractList | To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label extension (OLE) of the randomized, placebo-controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.
Patients who completed the randomized trial enrolled to receive CBD (Epidiolex
in the United States; Epidyolex
in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC-associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC).
Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1-57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One-year retention rate was 79%. Median treatment time was 267 days (range, 18-910) at a 27 mg/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-week windows across 48 weeks) were 54%-68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%-61%, 29%-45%, and 6%-11% across 12-week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks.
In patients with TSC, long-term add-on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement. To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label extension (OLE) of the randomized, placebo-controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.OBJECTIVETo evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label extension (OLE) of the randomized, placebo-controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.Patients who completed the randomized trial enrolled to receive CBD (Epidiolex® in the United States; Epidyolex® in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC-associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC).METHODSPatients who completed the randomized trial enrolled to receive CBD (Epidiolex® in the United States; Epidyolex® in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC-associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC).Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1-57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One-year retention rate was 79%. Median treatment time was 267 days (range, 18-910) at a 27 mg/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-week windows across 48 weeks) were 54%-68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%-61%, 29%-45%, and 6%-11% across 12-week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks.RESULTSOf 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1-57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One-year retention rate was 79%. Median treatment time was 267 days (range, 18-910) at a 27 mg/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-week windows across 48 weeks) were 54%-68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%-61%, 29%-45%, and 6%-11% across 12-week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks.In patients with TSC, long-term add-on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement.SIGNIFICANCEIn patients with TSC, long-term add-on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement. ObjectiveTo evaluate the long‐term safety and efficacy of add‐on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open‐label extension (OLE) of the randomized, placebo‐controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.MethodsPatients who completed the randomized trial enrolled to receive CBD (Epidiolex® in the United States; Epidyolex® in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC‐associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC).ResultsOf 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1–57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One‐year retention rate was 79%. Median treatment time was 267 days (range, 18–910) at a 27 mg/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‐week windows across 48 weeks) were 54%–68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%–61%, 29%–45%, and 6%–11% across 12‐week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks.SignificanceIn patients with TSC, long‐term add‐on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement. Objective To evaluate the long‐term safety and efficacy of add‐on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open‐label extension (OLE) of the randomized, placebo‐controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported. Methods Patients who completed the randomized trial enrolled to receive CBD (Epidiolex® in the United States; Epidyolex® in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC‐associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC). Results Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1–57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One‐year retention rate was 79%. Median treatment time was 267 days (range, 18–910) at a 27 mg/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‐week windows across 48 weeks) were 54%–68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%–61%, 29%–45%, and 6%–11% across 12‐week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks. Significance In patients with TSC, long‐term add‐on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement. |
| Author | Sparagana, Steven Filloux, Francis Kwan, Patrick Sahebkar, Farhad Loftus, Rachael Thiele, Elizabeth A. Wheless, James Bebin, E. Martina |
| AuthorAffiliation | 4 Monash University and the University of Melbourne Melbourne Victoria Australia 6 Greenwich Biosciences, Inc. Carlsbad California USA 5 GW Research Ltd Cambridge UK 3 University of Utah School of Medicine Salt Lake City Utah USA 7 Scottish Rite for Children and the University of Texas Southwestern Medical Center Dallas Texas USA 8 Le Bonheur Children's Hospital and the University of Tennessee Health Science Center Memphis Tennessee USA 2 University of Alabama School of Medicine Birmingham Alabama USA 1 Massachusetts General Hospital Boston Massachusetts USA |
| AuthorAffiliation_xml | – name: 6 Greenwich Biosciences, Inc. Carlsbad California USA – name: 2 University of Alabama School of Medicine Birmingham Alabama USA – name: 7 Scottish Rite for Children and the University of Texas Southwestern Medical Center Dallas Texas USA – name: 4 Monash University and the University of Melbourne Melbourne Victoria Australia – name: 5 GW Research Ltd Cambridge UK – name: 1 Massachusetts General Hospital Boston Massachusetts USA – name: 3 University of Utah School of Medicine Salt Lake City Utah USA – name: 8 Le Bonheur Children's Hospital and the University of Tennessee Health Science Center Memphis Tennessee USA |
| Author_xml | – sequence: 1 givenname: Elizabeth A. orcidid: 0000-0003-3431-4713 surname: Thiele fullname: Thiele, Elizabeth A. email: ethiele@mgh.harvard.edu organization: Massachusetts General Hospital – sequence: 2 givenname: E. Martina orcidid: 0000-0003-1264-3428 surname: Bebin fullname: Bebin, E. Martina organization: University of Alabama School of Medicine – sequence: 3 givenname: Francis surname: Filloux fullname: Filloux, Francis organization: University of Utah School of Medicine – sequence: 4 givenname: Patrick orcidid: 0000-0001-7310-276X surname: Kwan fullname: Kwan, Patrick organization: Monash University and the University of Melbourne – sequence: 5 givenname: Rachael surname: Loftus fullname: Loftus, Rachael organization: GW Research Ltd – sequence: 6 givenname: Farhad surname: Sahebkar fullname: Sahebkar, Farhad organization: Greenwich Biosciences, Inc – sequence: 7 givenname: Steven surname: Sparagana fullname: Sparagana, Steven organization: Scottish Rite for Children and the University of Texas Southwestern Medical Center – sequence: 8 givenname: James orcidid: 0000-0002-4735-3431 surname: Wheless fullname: Wheless, James organization: Le Bonheur Children's Hospital and the University of Tennessee Health Science Center |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34957550$$D View this record in MEDLINE/PubMed |
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To evaluate the long‐term safety and efficacy of add‐on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC)... To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the... ObjectiveTo evaluate the long‐term safety and efficacy of add‐on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC)... |
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| SubjectTerms | Adolescent Adult Anticonvulsants - adverse effects antiseizure medication Appetite loss Cannabidiol Cannabidiol - adverse effects Cannabinoids Caregivers Child Child, Preschool Convulsions & seizures Diarrhea epilepsy focal seizures Humans Infant Middle Aged Patients Seizures Seizures - drug therapy Seizures - etiology Treatment Outcome treatment‐resistant epilepsy Tuberous sclerosis Tuberous Sclerosis - complications tuberous sclerosis complex Valproic acid Young Adult |
| Title | Long‐term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open‐label extension trial |
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