Cannabidiol in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study

Abstract

Objective: Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial.

Methods: Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit.

Results: This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale.

Significance: In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

Keywords: antiepileptic drug; cannabinoid; childhood-onset epilepsy; drop seizures.

Figure 1

Patient disposition. LGS, Lennox‐Gastaut syndrome. ^aWithdrawals are shown by the primary reason for each patient

Figure 2

Reduction from baseline^a in (A) drop seizure frequency and (B) total seizure frequency. CBD, cannabidiol; IQR, interquartile range. ^aReduction from baseline of parent randomized trial. ^bPooled data from randomized controlled trials during 14‐wk treatment period (2‐wk titration followed by 12‐wk maintenance); n = 235 patients in CBD group includes patients receiving 10 and 20 mg/kg/d CBD

Figure 3

Responder rates at (A) drop and (B) total seizure reduction thresholds

Figure 4

Patient/caregiver ratings of overall condition on the S/CGIC scale. S/CGIC, Subject/Caregiver Global Impression of Change. ^aOf the 366 patients who enrolled in study (all of whom enrolled early enough to complete 24 wks of treatment), 72% reported improvement in overall condition after 24 wks of treatment