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

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.

Time to onset of cannabidiol treatment effects in Dravet syndrome: Analysis from two randomized controlled trials

“…The interpretability and generalizability of the results are limited mostly because it was a post hoc analysis of pooled data from two trials with a rigid titration schedule. Although the observation of an early/clear separation from placebo may not prove to be statistically significant in a prospectively designed trial, the evidence of an early CBD antiseizure effect in two other post hoc analyses of trials in LGS 24 and TSC 25 robustly supports our results of an early antiseizure effect in DS. We could not evaluate the by‐day onset of efficacy for patients taking versus not taking clobazam due to the small number of patients not taking clobazam combined with the highly variable seizure data from just the first few days of treatment (compared to the full 14‐week treatment period); such an analysis would require a more appropriately powered study with balanced subgroups.…”

Long‐term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open‐label extension trial

“…Although the etiology is not known, diarrhea has been reported as the most frequent AE in other clinical trials of CBD; in most cases, however, the severity was mild or moderate and resolved before the end of treatment. 30 , 31 Permanent treatment discontinuation because of an AE was low (6%) despite some patients being on treatment for up to 130 weeks, supporting a favorable safety profile of CBD for long‐term use in patients with TSC‐associated seizures.…”

Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine

“…Findings from a post hoc analysis suggested that the onset of the treatment effect occurred early, within the first 2 weeks. 101 Longer-term adjunctive CBD treatment has been evaluated in an OLE to the GWPCARE6 study, involving 199 of the 201 patients who completed the RCT. 77 Reductions in seizures were maintained through 48 weeks, at least 6% of patients remained seizure free during the 12-week windows, and improvement in S/CGIC continued to be reported by a high proportion of proportion of patients/caregivers (Table 2; Figure 3).…”

“…A post hoc analysis reported that AEs lasted longer for CBD versus placebo but resolved within the 16-week study in most patients. 101 Furthermore, results from a real-world study have suggested that slow titration of CBD can deliver improved tolerance with comparable efficacy. 102 The AE profile over the long-term in the OLE was similar to that observed previously.…”

“…Findings from a post hoc analysis suggested that the onset of the treatment effect occurred early, within the first 2 weeks. 101…”