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.
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.
© 2019 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.
Conflict of interest statement
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.
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.
Keywords: antiepileptic drug; cannabinoid; childhood-onset epilepsy; drop seizures.
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.
Dr. Patel, who is also an associate professor of Clinical Pediatrics and Neurology at The Ohio State University College of Medicine, says the results are reassuring and encouraging. He is curious to see what other ongoing trials will reveal about the benefits of a prescription based CBD in additional populations of epilepsy patients as well as other diseases, such as autism or anxiety.
Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. It is characterized by multiple seizure types, developmental delay or intellectual disability, and abnormal electroencephalographic patterns, with onset typically before age 7 years.
Based on evidence from animal studies and case reports, researchers at Nationwide Children’s and other institutions began investigating highly purified cannabidiol (CBD) for the treatment of seizures. In two randomized, double-blind, placebo-controlled trials, CBD significantly reduced seizure frequency and had an acceptable safety profile in LGS patients.
CBD treatment also resulted in sustained reductions in total seizures up to 156 weeks, with 87% or more of patients/caregivers reporting an improvement in overall condition.
In 2018, this highly purified plant-based CBD was approved by the Food and Drug Administration for the treatment of certain seizure disorders (including LGS), becoming the first plant-based marijuana derivative ever approved for human disease in the United States.
However, the potential long-term benefits or harms of CBD were unknown. To answer these questions, researchers from Nationwide Children’s and elsewhere invited patients who completed the original randomized, controlled trials to participate in a long-term open-label extension trial of the treatment. A total of 366 patients with LGS were enrolled in this trial across 53 sites in the United States and Europe.
Results demonstrated that long-term CBD treatment had a similar safety profile to that observed in the original randomized controlled trials, with the most common adverse effects being convulsion, diarrhea, fever, fatigue and vomiting.
“We were pleased to see the results indicated continued treatment success and no new side effects,” says Anup Patel, MD, a pediatric neurologist at Nationwide Children’s and the study’s lead author.
The results of a long-term open-label extension trial of plant-derived, highly purified cannabidiol (CBD) show the treatment is effective and safe long term for patients with Lennox-Gastaut syndrome. The treatment had a similar safety profile as in the original randomized controlled trials and resulted in a similar drop in seizure frequency for up to 156 weeks.
3 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
Joon Soo Lee
In this first Korean study, CBD was safe and tolerable for use and could be expected to potentially reduce the seizure frequency in pediatric patients with LGS or DS.
Drowsiness and other adverse events, such as elevated liver enzymes, that have been reported in some studies7 were thought to be essential for confirming the interaction between CBD and antiepileptic drugs such as VPA and clobazam (CLB) through further research; the reason for this is that the metabolism of CBD by the liver can inhibit cytochrome P450. This affects the metabolism of some antiepileptic drugs; in the case of CLB, it can increase the serum level of N-desmethylclobazam, which is an active metabolite of CLB.8,21,22,23,24