Adding a purified formulation of cannabidiol (CBD; Epidiolex, GW Pharmaceuticals) to standard anticonvulsant therapy significantly reduces the number of drop seizures in children with resistant Lennox-Gastaut syndrome (LGS), results of a phase 3 randomized, double-blind, placebo-controlled clinical trial show.
“We saw similar efficacy in the expanded-access program but, of course, there was criticism of that because it wasn’t randomized, placebo-controlled; it was open-label. So I was very pleased to see the results of this phase 3 trial,” lead investigator, Elizabeth A. Thiele, MD, PhD, director, Pediatric Epilepsy Program, Massachusetts General Hospital, and professor, neurology, Harvard Medical School, Boston, told Medscape Medical News.
The study was published online January 24 in The Lancet.
Meaningful Improvements
LGS is a relatively rare type of epilepsy that typically develops between ages 3 and 5 years and is very drug resistant. Patients with LGS often have multiple seizures types, including drop seizures. These are usually very brief atonic seizures in which the muscles suddenly become limp, causing head nods, loss of posture, and falling to the ground.
The phase 3 study, conducted at 24 sites in the United States, the Netherlands, and Poland, included 171 patients (mean age, 15.4 years) with highly treatment-resistant LGS. At baseline, they had previously not responded to a median of six antiepileptic drugs, were taking a median of three concomitant antiepileptic drugs, and had a median of 73.8 drop seizures every 28 days.
Eighty-six participants were randomly allocated to the oral purified formulation of CBD (20 mg/kg/day) and 85 to matching placebo taken concomitantly with their usual anticonvulsant medication for 14 weeks.
“Even in this highly treatment-resistant population, statistically significant and clinically meaningful improvements in seizure frequency were observed following the addition of cannabidiol to existing antiepileptic drug regimens compared with placebo,” the investigators report.
During the 14-week treatment period (2-week dose escalation period followed by 12 weeks of maintenance), patients taking CBD had a significantly greater median reduction in drop seizures (the primary endpoint) compared with those receiving placebo (44% vs 22%; P = .0135).
Sensitivity analyses confirmed that the treatment effect of CBD was established during the first month of treatment and was sustained over the entire treatment period.
Results from key secondary endpoints indicate that significantly more patients receiving CBD experienced a 50% or greater reduction in drop seizures compared with those taking placebo (44% vs 24%; P = .0043) and total seizure frequency was significantly reduced with CBD compared with placebo (median reduction, 41% vs 14%; P = .0005).
Patients and caregivers were significantly more likely to report an improvement in overall condition with CBD than placebo (58% vs 34%; odds ratio, 2.54 [95% confidence interval, 1.5 – 4.5; P = .0012]) based on the Subject/Caregiver Global Impression of Change scale.
Reassuring Findings
Dr Thiele said the efficacy of CBD in this trial, a previous LGS trial and one in Dravet syndrome are all “very similar, which is very reassuring.”
Add-on CBD was generally well tolerated. The most common adverse events (AEs) (>10%) were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting. Overall, 86% of patients taking CBD and 69% of patients taking placebo experienced an AE. Most were mild or moderate, resolved on treatment, and were consistent with previous clinical trial reports of the use of CBD in patients with epilepsy, the investigators note
AEs led to study withdrawal in 12 (14%) patients in the CBD group and 1 (1%) patient in the placebo group. The most frequent AEs leading to withdrawal were transient elevations in liver enzymes. The investigators note that 16 of 20 patients in the CBD group with elevated transaminases levels were receiving valproate. It would be “prudent for clinicians to monitor transaminases in all patients taking concomitant cannabidiol and valproate,” they note.
The current study also confirms prior observations of a potential interaction between CBD and the antiepileptic drug clobazam.
“Clinicians might choose to observe patients on concomitant clobazam and adjust doses as necessary to manage adverse events; during this trial clobazam dose was decreased in 27% of patients in the cannabidiol group,” the investigators write.
“Characterizing the drug-drug interactions is important, and I think that’s really been done nicely by GW Pharmaceuticals and by all the sites involved in the expanded access program,” said Dr Thiele.
“We know there is a drug interaction with clobazam. CBD affects the metabolism of clobazam, so there can be a significant elevation in an active metabolite of clobazam. That can result in significant drowsiness or sometimes, much less commonly, agitation. We also know there is an interaction with valproate. These are important to know because these are widely used medications,” she said.
There were no instances of abuse or misuse of CBD in the study.
Exciting Time in Epilepsy
Writing in a linked comment, Sophia Varadkar, MRCPI, PhD, from the Neuroscience Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom, says after many years without promise of new treatments in LGS, “This is an exciting time for patients and clinicians…. The study by Thiele and colleagues contributes to the evidence base for cannabidiol as a treatment for patients with drop seizures associated with Lennox-Gastaut syndrome but also highlights why further studies are needed.”
The study assessed a single target daily CBD dose of 20 mg/kg.
“Higher doses might have greater efficacy, lower doses might have fewer side-effects, and varying doses according to concomitant antiepileptic drugs might minimise drug-drug interactions,” Dr Varadkar points out. “We also need to determine the best stage in the treatment pathway of Lennox-Gastaut syndrome to introduce cannabidiol and how cannabidiol will relate to non-pharmacological interventions, such as ketogenic diet and vagus nerve stimulation.”
Dr Varadkar also notes that the treatment period does not provide data on medium-term or longer-term tolerability or whether responses to cannabidiol will be sustained. “The ongoing open-label extension study…might answer these questions,” Dr Varadkar says.
A new drug application for Epidiolex in the treatment of LGS and Dravet syndrome is pending at the US Food and Drug Administration, with action expected in late June of this year. If approved, Epidiolex is expected to be available in the United States by prescription in the second half of 2018, the company said.
The study was funded by GW Pharmaceuticals. Several authors have financial relationships with the company. All are listed with the original article. Dr Varadkar has participated as an expert clinical adviser in a National Institute for Health and Care Excellence scoping workshop on cannabidiol for adjuvant treatment of seizures associated with Dravet syndrome or LGS, representing the International League Against Epilepsy British Chapter in 2018.
Lancet. Published online January 24, 2018. Abstract, Comment
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