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Randomized Controlled Trial
. 2019 Mar;60(3):419-428.
doi: 10.1111/epi.14670. Epub 2019 Feb 11.

Cannabidiol in Patients With Lennox-Gastaut Syndrome: Interim Analysis of an Open-Label Extension Study

Affiliations
Free PMC article
Randomized Controlled Trial

Cannabidiol in Patients With Lennox-Gastaut Syndrome: Interim Analysis of an Open-Label Extension Study

Elizabeth Thiele et al. Epilepsia. .
Free PMC article

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.

Conflict of interest statement

Elizabeth Thiele has served as a study investigator for GW Pharmaceuticals. Eric Marsh has served as a consultant for Eisai Pharma and Cydan, and as a study investigator for GW Pharmaceuticals. Maria Mazurkiewicz‐Beldzinska has served as a study investigator for GW Pharmaceuticals. Jonathan J. Halford has served as a consultant for Brain Sentinel and as a study investigator for GW Pharmaceuticals. Boudewijn Gunning has served as a study investigator for GW Pharmaceuticals. Orrin Devinsky has served as a consultant/advisor to GW Pharmaceuticals and Pairnomix, and as a study investigator for GW Pharmaceuticals, has equity interest in Tevard, Empatica, Privateer Holdings, and Receptor Life Sciences and has equity ownership of Papa & Barkley. Daniel Checketts is employed by GW Research Ltd. Claire Roberts was employed by GW Research Ltd at the time of this study and is now affiliated with Eisai Ltd. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

Figure 1
Figure 1
Patient disposition. LGS, Lennox‐Gastaut syndrome. aWithdrawals are shown by the primary reason for each patient
Figure 2
Figure 2
Reduction from baselinea 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
Figure 3
Responder rates at (A) drop and (B) total seizure reduction thresholds
Figure 4
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

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