Abstract
Objective: To assess adverse events (AEs) and efficacy of add-on cannabidiol (CBD) with a slower titration protocol in pediatric clinical practice.Methods: We conducted a prospective, open-label, multicenter study in seven French reference centers for rare epilepsies. Patients had slow titration to reach a target dose of 10 mg/kg/day within at least 1 month and then gradually increased to a maximum dose of 20 mg/kg/day. We analyzed AEs and efficacy at M1 (month 1), M2, and M6, comparing two sets of subgroups: Dravet syndrome (DS) vs. Lennox-Gastaut (LGS) and patients with clobazam (CLB+) vs. patients without (CLB−).Results: One hundred and twenty-five patients were enrolled (62 LGS, 48 DS, 5 Tuberous sclerosis, and 10 other etiologies). Median concomitant antiepileptic drugs (AEDs) was three (25th percentile: 3, 75th percentile: 4). Patients received a dose of 10 (10–12), 14 (10–20), and 15.5 mg/kg/day (10–20) at M1, M2, and M6, respectively. Twenty-six patients discontinued CBD, 19 due to lack of efficacy, 2 due to AEs, 4 for both, and 1 had a sudden unexpected death in epilepsy. AEs were reported in 61 patients (48.8%), mainly somnolence (n = 26), asthenia (n = 20), and behavior disorders (n = 16). Abnormal transaminases (≥3 times) were reported in 11 patients receiving both valproate and clobazam. AEs were significantly higher at M2 (p = 0.03) and increased with the number of AEDs (p = 0.03). At M6, total seizure frequency change from baseline was −41% ± 37.5% (mean ± standard deviation), and 28 patients (37.8%) had a reduction ≥50%. AE and efficacy did not differ between DS vs. LGS and CLB+ vs. CLB– patients.Significance: A slower titration of CBD dose delivered better tolerance with comparable efficacy to previous trials. Concomitant CLB did not increase efficacy rates but in a few cases increased AEs. This slow titration scheme should help guide clinicians prescribing CBD and allow patients to benefit from its potential efficacy.
Highlights
Since June 2018, an oil-based, highly purified, liquid formulation of cannabidiol (CBD, Epidiolex R in the United States, Epidyolex R in the European Union) was approved by the Food and Drug Administration (FDA) for the treatment of seizures associated with DS and LGS in individuals 2 years of age and older (1)
AEs were reported in 61 patients (48.8%) during the whole period of follow-up
The profile of our population was close to those described in randomized controlled trials (RCT) and open-label studies (OL) in terms of epileptic syndrome, sex ratio, number of antiepileptic drug (AED) per patient, age, and main treatments associated with CBD (Supplementary Table 1) (6–9, 11, 14–16)
Summary
Since June 2018, an oil-based, highly purified, liquid formulation of cannabidiol (CBD, Epidiolex R in the United States, Epidyolex R in the European Union) was approved by the Food and Drug Administration (FDA) for the treatment of seizures associated with DS and LGS in individuals 2 years of age and older (1). In France, CBD had been available since December 2018 in the form of a nominative “temporary authorization for use” (ATU) (2) and more recently (September 2019) via marketing authorization of Epidyolex R by the European Medicines Agency (EMA) (3). The indication was given for “adjunctive therapy of seizures associated with LGS and DS, in conjunction with clobazam (CLB), for patients 2 years of age and older” (3). Within the nominative ATU (ATUn) use, prescription of CBD has been extended to selected drug-resistant patients.
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