Assistant Professor of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Cornell Medical College
Dr. Kandula reports no financial relationships relevant to this field of study.
SYNOPSIS: In this double-blind, placebo-controlled trial, the authors investigated the efficacy of adjunctive cannabidiol in a population of severe developmental epileptic encephalopathies and found some efficacy.
SOURCE: Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med 2018;378:1888-1897.
The International League Against Epilepsy recognizes more than 20 different epilepsy syndromes, defined as a distinctive combination of clinical features, signs, electrographic patterns, and age of onset. Lennox-Gastaut syndrome is a severe epileptic encephalopathy defined by multiple seizure types, particularly tonic and atypical absence seizures, but also atonic and myoclonic seizures. The disorder also is characterized by a distinctive diffuse slow (less than 3 Hz) spike-and-wave pattern on electroencephalogram (EEG). Seizures occur generally before age 8 years, and patients are left with severe cognitive impairment. Although six broad-spectrum anticonvulsants are approved for the treatment of the various seizure types, no particular drug has been shown to be highly effective. Despite pharmacologic treatment, most patients remain medication-resistant with poor neurologic outcome. Drop seizures caused by an increase in motor tone (tonic) or loss of tone (atonic) are particularly troublesome because of the risk of injury in these patients. In addition to traditional anticonvulsant therapy, vagus nerve stimulation, ketogenic diet, and corpus callosotomy also have been used with some success. More recently, an open-label trial of cannabidiol in severe, intractable, childhood-onset, treatment-resistant epilepsy was promising for efficacy and relative safety in drug-resistant epilepsy. These same authors have embarked on a double-blind, placebo-controlled trial to assess the effectiveness and safety of adjunctive low and high doses of cannabidiol specifically on drop seizures in Lennox-Gastaut syndrome.
Thirty participating sites recruited patients over a seven-month interval in 2015. The Phase III trial was structured with a baseline four-week period, a 14-week treatment period, and a 10-day tapering period. A four-week follow-up period after cannabidiol or placebo was discontinued also was included. Patients were followed for up to 24 weeks.
Lennox-Gastaut patients were eligible for the trial if they were between 2 and 55 years of age with characteristic slow spike-and-wave discharges on EEG and at least two types of generalized seizures, including drop seizures (tonic, atonic, tonic-clonic) for at least six months. Eligible patients required at least two drop seizures weekly during the baseline period. All pharmacologic and non-pharmacologic treatments (ketogenic diet, vagus nerve stimulator) were stable during the four weeks before screening and during the trial. Concurrent use of recreational or medicinal cannabis in the prior three months, use of corticotropins in the last six months, or felbamate within the last year were excluded.
Eligible patients were assigned to one of four groups: cannabidiol at 20 mg/kg, cannabidiol at 10 mg/kg, or matching placebo for both the 20 mg/kg and 10 mg/kg groups. The active ingredient was a plant-derived pharmaceutical formulation of purified cannabidiol oral solution (100 mg/mL) administered twice daily. Patients and their caregivers recorded number and types of seizures daily as well as adverse events. Office visits occurred at two, four, eight, and 14 weeks after randomization. Follow-up telephone calls at six and 10 weeks post-cannabidiol or placebo taper also were made.
The primary outcome was absolute percentage change from baseline in frequency in drop seizures. Key secondary outcomes were 50% reduction from baseline in drop seizures, percent change from baseline in frequency of all seizure types, and the patient/caregiver global impression of change from baseline. Additional secondary outcomes included 25%, 75%, and 100% reduction from baseline in drop seizures.
Ultimately, 225 patients were included in the study: 76 patients were assigned to the 20 mg/kg cannabidiol group, 73 patients were assigned to the 10 mg/kg cannabidiol group, and 76 were assigned to the placebo group.
The median reductions in drop seizures were 41.9% for the 20 mg/kg group, 37.2% for the 10 mg/kg group, and 17.2% for the placebo group. Thirty-nine percent in the 20 mg/kg group, 36% in the 10 mg/kg group, and 14% in the placebo group had at least 50% drop seizure reduction from baseline. Although not a key secondary outcome, the median percent reduction in non-drop seizures was 61.1% for the 20 mg/kg group, 54.6 for the 10 mg/kg group, and 34.3% for the placebo group. Caregiver global impression of change was 57% in the 20 mg group, 66% in the 10 mg group, and 44% in the placebo group.
Adverse events were common in all groups. Ninety-four percent of patients in the 20 mg group, 84% in the 10 mg group, and 72% in the placebo group most commonly reported somnolence, decreased appetite, diarrhea, upper respiratory symptoms, pyrexia, and vomiting. The investigators classificed most adverse effects as mild. However, seven patients were withdrawn from the trial for elevated liver transaminase three to 12 times the upper limit of normal. Fourteen patients had elevated liver enzymes at three times the upper limit of normal. Of these 14 patients, 11 were receiving concurrent valproate therapy.
Cannabidiol represents an interesting adjunctive treatment for severe drug-resistant epileptic encephalopathies. The perceived “naturalistic” effect of the agent also is appealing to both caregivers and patients. However, although the initial results are promising, there are some methodological limitations. All quantification of seizure types was dependent solely on caregiver or patient report without EEG confirmation. There was no statistical difference in global impression of change (slightly improved, much improved, or very much improved) between both cannabidiol and placebo groups, raising the question of large placebo effect. Also, it is difficult to separate individual drug effects. Nearly 40-50% of patients were on polypharmacy with either valproic acid or clobazam treatment. The P450 2C19 effect of cannabidiol is known to inhibit clobazam. Hence, the increase in active metabolite calls into question the enhanced effect from clobazam that may not be attributable entirely to cannabidiol. In previous trials, the 50% responder rates for vagus nerve stimulation and clobazam treatment were similar if not better than both doses of the cannabidiol treatment groups. Additionally, it is unclear whether the liver enzyme elevation was independent of cannabidiol effect or enhanced from valproic acid adjunctive therapy. Although the epileptic encephalopathies represent a challenging population in need of additional therapeutic options, there are still many unresolved questions regarding cannabidiol efficacy and safety.