Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome

Abstract

IMPORTANCE Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose.OBJECTIVE To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome. DESIGN, SETTING, AND PARTICIPANTSThis double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) recruited patients from April 13, 2015, to November 10, 2017, with follow-up completed on April 9, 2018. Of 285 patients screened from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel, 86 were excluded, and 199 were randomized. Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug. Data were analyzed from November 16 (date of unblinding) to December 13 (date of final outputs), 2018, based on intention to treat and per protocol. MAIN OUTCOMES AND MEASURESThe primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score. RESULTSOf 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%; P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%; P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium.CONCLUSIONS AND RELEVANCE Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety.

Clinical implications of trials investigating drug‐drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs

“…Death, n (%) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) was equivalent to the highest maintenance dose used in recent phase 3 trials in DS and LGS. [12][13][14][15] These results may therefore inform treatment decisions when concomitant treatment of CBD with enzyme inducers or inhibitors or other ASDs is considered.…”

“…There were no clinically important DDIs between CBD and VPA or its metabolite, 4-ene-VPA, in healthy volunteers or patients with epilepsy. 35,37 Dose-related elevations in transaminase levels with CBD are more common in patients who receive concomitant VPA [11][12][13][14][15]45 ; as 4-ene-VPA has been associated with hepatotoxicity, [27][28][29] it is important to measure plasma levels of both compounds. If such elevations occur, discontinuation or reduction of CBD and/or concomitant VPA should be considered for patients receiving both drugs.…”

“…However, there is significant clinical experience and safety information in pediatric populations (≥2 years of age) when CBD is given in combination with multiple ASDs. [12][13][14][15] From 1 year of age, CYP450 activity and expression are considered to be close to adult levels for the majority of major CYP450 isoforms. 50 It is therefore expected that patients older than 1 year are adequately exposed to administered drugs, are not compromised in their capacity to metabolize CBD or other concomitant medications, and would not require dose modification different from that of adults in the case of CYP-mediated DDIs.…”

Cannabidiol and Abnormal Liver Chemistries in Healthy Adults: Results of a Phase I Clinical Trial

“…5 In all the CBD RCTs, liver safety concerns arose following the frequent occurrence of elevations in serum alanine aminotransferase (ALT). [1][2][3][4][5] These events typically first occurred in the first 2 months of treatment initiation. 6 Serum alkaline phosphatase (ALP) elevations were uncommon, [1][2][3][4] consistent with a hepatocellular injury.…”

Multi-Omic Analysis Reveals Disruption of Cholesterol Homeostasis by Cannabidiol in Human Cell Lines

“…The non-psychoactive cannabinoid, cannabidiol (CBD), was recently approved by the FDA for treatment of two drug-resistant epileptic disorders, Lennox-Gastaut syndrome and Dravet syndrome (Devinsky et al, 2017;Miller et al, 2020;Thiele et al, 2018). CBD has an encouraging safety profile across multiple human clinical trials, which has fueled increased interest in CBD as a therapeutic in other disorders (Iffland and Grotenhermen, 2017).…”