Authors :
Stéphane Auvin, MD, PhD – Pediatric Neurology Department & INSERM U1141, Robert-Debré University Hospital, APHP, Paris, France; Charlotte Nortvedt, MSc, BSc – Jazz Pharmaceuticals, Inc., London, UK; Douglas S. Fuller, MS – Jazz Pharmaceuticals, Inc., Palo Alto, California, USA; Farhad Sahebkar, MD – Jazz Pharmaceuticals, Inc., Palo Alto, California, USA
Rationale: Drop seizure count is commonly used as an established primary endpoint for clinical trials in Lennox-Gastaut syndrome (LGS). However, the use of drop seizure count as a primary endpoint is frequently criticized by experts, as this does not allow for evaluation of impact on quality of life or total seizure burden. Here, we seek to evaluate the number of days without a drop seizure as a potential new outcome measure to demonstrate the efficacy of antiseizure medications (ASMs) in patients with LGS.
Methods: A post hoc analysis of two phase 3, randomized, double-blind, placebo-controlled trials in patients with LGS (GWPCARE3, NCT02224560; GWPCARE4, NCT02224690) was performed. In both trials, patients were randomly assigned to receive plant-derived highly purified cannabidiol (CBD) (Epidiolex®; 100 mg/mL oral solution) at 10 mg/kg/day (CBD10; GWPCARE3 only) or 20 mg/kg/day (CBD20), or matched placebo, in addition to their current ASMs. The treatment period consisted of a 2‑week titration period followed by a 12-week maintenance period. This post hoc analysis evaluated the change from baseline in the number of drop seizure-free days per 28 days. Results are reported for the intention-to-treat population during the treatment period. Least-squares (LS) mean changes from baseline in drop seizure-free days and difference versus placebo were estimated using an analysis of covariance model with baseline number of drop seizure-free days and categorical age as covariates, and treatment group as a fixed factor.
Results: In total, 396 patients were included in the analyses. The median (range) age was 13 (3–48) years and 55% of the patients were male. Patients had previously taken a median (range) of 6 (0–28) ASMs and were taking a median (range) of 3 (0–5) concomitant ASMs. For patients receiving CBD10 (n=73) and CBD20 (n=162) the LS mean (95% confidence interval [95% CI]) changes from baseline in number of drop seizure-free days per 28 days were 5.64 (4.08–7.20) and 6.45 (5.39–7.52; Table 1). A greater increase in LS mean (95% CI) number of drop seizure-free days compared with placebo was observed with both CBD10 (2.83 [0.98–4.68]; p=0.0028) and CBD20 (3.64 [2.18–5.10; p< 0.0001]; Table 1
Conclusions: In this post hoc analysis of GWPCARE3 and GWPCARE4, the evaluated novel endpoint of drop seizure-free days demonstrated improvements from baseline overall and versus placebo at both doses of CBD. As such, this parameter represents a potential new endpoint for seizure assessment in patients with LGS for future clinical trials.
Funding: These trials were funded by GW Research Ltd., now part of Jazz Pharmaceuticals, Inc.