Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial

Abstract

Importance: Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC).

Objective: To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC.

Design, setting, and participants: This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication.

Interventions: Patients received oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks.

Main outcomes and measures: The prespecified primary outcome was the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period.

Results: Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo.

Conclusions and relevance: Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage.

Trial registration: ClinicalTrials.gov Identifier: NCT02544763.

Figure 1.. Screening, Randomization, and Treatment Period

^aPatients may have more than 1 reason for exclusion. ^bPatients had adverse event as the primary reason for discontinuation. ^cOne patient in the 25–mg/kg/d cannabidiol group discontinued treatment because of difficulty taking the study medication, problems with eating and drinking, occurrence of constipation, and increase in seizures. ^dTwo patients in the 50–mg/kg/d cannabidiol group met the withdrawal criteria via elevations in alanine aminotransferase or aspartate aminotransferase levels.

Figure 2.. Seizure Outcomes During the Treatment Period

A, Reduction from baseline in the frequency of primary–end-point and total seizures. B, Proportion of patients with a 50% or more and 75% or more reduction from baseline in primary–end-point seizures. Negative binomial regression was used to compare seizure frequency between cannabidiol groups with placebo. The treatment period (16 weeks) constituted the titration and maintenance phases. The estimated ratio of least squares means for the treatment period to baseline period was used to evaluate the reduction in seizure frequency. The P values for the testing of the null hypothesis that the estimated ratio of each cannabidiol group to placebo was 1 are presented. The primary–end-point seizures are all countable focal motor seizures without impairment of awareness, focal seizures with impairment of awareness, focal seizures evolving to bilateral motor seizures, and generalized seizures (tonic-clonic, tonic, clonic, or atonic). Total seizures include all types combined, including focal sensory seizures and epileptic spasms. The odds ratios are presented for the comparisons in a 50% responder rate between the placebo group and the groups receiving 25–mg/kg/d and 50–mg/kg/d of cannabidiol. The P values were calculated from a Cochran–Mantel-Haenszel test stratified by age group (1-6, 7-11, 12-17, and 18-65 years). The percentage reduction in primary–end-point seizures from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) in the cannabidiol 25 mg/kg/day (CBD25) group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) in the cannabidiol 50 mg/kg/day (CBD50) group. The percentage reduction in total seizures from placebo was 29.1% (95% CI, 12.7% to 42.4%; nominal P = .001) in the CBD25 group and 28.4% (95% CI, 11.8% to 41.8%; nominal P = .002) in the CBD50 group. Note: the P values displayed in the Figure are nominal values.

Figure 3.. Change From Baseline in Frequency of Primary–End-Point Seizures During the Treatment Period in Patients Taking Cannabidiol Without Clobazam and With Clobazam

Negative binomial regression was used to compare seizure frequency between the cannabidiol groups with the placebo group. The treatment period (16 weeks) constituted the titration and maintenance phases. The estimated ratio of least squares means for treatment period to baseline period was used to evaluate the reduction in seizure frequency. The primary–end-point seizures are all countable focal motor seizures without impairment of awareness, focal seizures with impairment of awareness, focal seizures evolving to bilateral motor seizures, and generalized seizures (tonic-clonic, tonic, clonic, or atonic). The percentage reduction from placebo was 24.7% (95% CI, 3.7%-41.1%) between placebo and cannabidiol 25 mg/kg/day (CBD25) groups and 22.0% (95% CI, −0.1% to 39.1%) between the placebo and cannabidiol 50 mg/kg/day (CBD50) groups among patients not taking clobazam and 46.6% (95% CI, 20.0%-64.4%) between the placebo and CBD25 groups and 46.6% (95% CI, 21.1%-63.9%) between the placebo and CBD50 groups among patients taking clobazam.