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(Abst. 2.296), 2015

Long-term efficacy and tolerability of add-on cannabidiol for drug-resistant pediatric epilepsies
Authors: Michael Oldham, Joseph Sullivan, Nilika Singhal, Nicole Tilton, Maria Cilio
Content: Rationale: Anecdotal reports and preliminary short-term data suggest that cannabidiol (CBD) can be effective in controlling seizures in various forms of childhood drug-resistant epilepsies. However, long-term studies on efficacy and safety are lacking, particularly in the pediatric population.Methods: Children with drug-resistant epilepsy were enrolled in a prospective observational study under an expanded access investigational new drug (IND) program, and treated with a pharmaceutical preparation of 98% CBD (Epidiolex, GW Pharma) in add-on to anti-epileptic drug (AED) regimen. The doses of AEDs remained unchanged during the first 3 months of treatment. All seizure types were video-EEG confirmed prior to enrollment. Parents maintained a seizure diary during a 4-week baseline period, as well as during treatment. After the baseline period, patients were started on 5mg/kg/day of CBD, and titrated weekly by 5mg/kg increments until intolerance or a maximum dose of 25mg/kg/day. Labs for hematologic, liver, kidney function, and AED trough levels were performed at baseline, and after 1, 2 and 3 months of CBD therapy. Median percent reduction in monthly seizure frequency was calculated at 3 and 12 months. Response was considered ≥50% seizure reduction.Results: Between January 2014 and December 2014, 25 patients were enrolled, 13 (52%) of whom were female. Mean age was 9 years (range 1-17 years). The mean number of AEDs was 2 (range 0-3). Seven patients (28%) had Dravet syndrome (DS). Epilepsy with myoclonic absences (EMA), CDKL5, and Lennox-Gastaut syndrome (LGS) each had 4 patients (16% each). Side effects were seen in 19 (76%) patients, the most common being food aversion (n=9), diarrhea (n=7), and weight loss (n=6), including a mean weight loss from baseline of 5% (range 1-15%). Increases in phenobarbital and clobazam levels were seen in 2 and 5 patients, respectively. There were no clinically significant changes in hematologic, liver or kidney function. Baseline seizure frequency was 70 seizures per month (range 5-3000). At 3-month follow-up, 8 (32%) patients responded to CBD. Three patients were seizure-free (2 with DS and 1 boy with CDKL5). Five patients had ≥50% seizure reduction (2 with LGS, 1 with DS, 1 with EMA, and 1 with focal symptomatic epilepsy). At 12-month follow-up, 10 (40%) patients had ≥50% seizure reduction. Only one patient remained seizure free who had DS. Twelve patients discontinued CBD due to lack of efficacy, and one patient due to a marked increase in seizure frequency deemed to be related to CBD.Conclusions: Add-on pure CBD was associated with more than 50% seizure reduction in one-third of patients at 3 months. This substantial improvement in seizure control was maintained in 40% of patient for 12 months. Best results were obtained in patients with Dravet syndrome, although one experienced a severe increase in seizure frequency. Weight loss, decreased appetite, and diarrhea were dose-dependent, and only partially resolved with a decrease in CBD dose.