Checketts, D. (Daniel)
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- Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome A Randomized Clinical Trial(2020) Gil-Nagel, A. (Antonio); Sanchez-Carpintero, R. (Rocío); Knappertz, V. (Volker); Saneto, R.P. (Russell P.); Dunayevich, E. (Eduardo); Checketts, D. (Daniel); Gunning, B. (Boudewijn); Miller, I. (Ian); Perry, M.S. (M. Scott); Scheffer, I.E. (Ingrid E.)Question Is adjunctive cannabidiol at doses of 10 and 20 mg/kg/d superior to placebo in reducing convulsive seizure frequency in patients with Dravet syndrome? Findings This double-blind clinical trial randomized 199 children with Dravet syndrome to cannabidiol (10 or 20 mg/kg/d) or matched placebo for 14 weeks. Convulsive seizure frequency compared with baseline was reduced by 48.7% in the 10-mg/kg/d cannabidiol group and 45.7% in the 20-mg/kg/d cannabidiol group vs 26.9% in the placebo group. Meaning Both doses of adjunctive cannabidiol were similarly efficacious in reducing convulsive seizures associated with Dravet syndrome.
- 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(Willey, 2022) Joshi, C. (Charuta); Devinsky, O. (Orrin); Sanchez-Carpintero, R. (Rocío); Sahebkar, F. (Farhad); Wu, J.Y. (Joyce Y.); Roberts, C. (Colin); Checketts, D. (Daniel); Cock, H.R. (Hanna R.); Miller, I. (Ian)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.
- Add-on cannabidiol in patients with Dravet syndrome: Results of a long-term open-label extension trial(Willey, 2021) Devinsky, O. (Orrin); Nabbout, R. (Rima); Sanchez-Carpintero, R. (Rocío); Shiloh-Malawsky, Y. (Yael); Halford, J.J. (Jonathan J.); Dunayevich, E. (Eduardo); Checketts, D. (Daniel); Miller, I. (Ian); Zolnowska, M. (Marta); Wong, M. (Matthew); Scheffer, I.E. (Ingrid E.)Objective: Add-on cannabidiol (CBD) reduced seizures associated with Dravet syndrome (DS) in two randomized, double-blind, placebo-controlled trials: GWPCARE1 Part B (NCT02091375) and GWPCARE2 (NCT02224703). Patients whocompletedGWPCARE1 PartA(NCT02091206)orPartB,orGWPCARE2,were enrolled in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. Methods: Patientsreceived a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/ml), titrated from 2.5 to 20 mg/kg/day over a 2-week period, added to their existing medications. Based on response and tolerance, CBD could be reduced or increased to 30 mg/kg/day. Results: Of the 330 patients who completed the original randomized trials, 315 (95%) enrolled in this open-label extension. Median treatment duration was 444 days (range = 18–1535), with a mean modal dose of 22 mg/kg/day; patients received a median of three concomitant antiseizure medications. Adverse events (AEs)occurredin97%patients(mild,23%;moderate,50%;severe,25%).Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty-eight (9%) patients discontinued due to AEs. Sixtynine (22%) patients had liver transaminase elevations >3 × upper limit of normal; 84% were on concomitant valproic acid. In patients from GWPCARE1 Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to Week 156 was 45%–74% for convulsive seizures and 49%–84% for total seizures. Across all visit windows, ≥83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition. Significance: We show that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductionsin seizure frequency in patients with treatment-resistant DS.