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(Abst. 3.181), 2017

Efficacy of Cannabidiol in Patients with Refractory Epilepsy Relative to Concomitant Use of Clobazam
Authors: Patricia Bruno, Massachusetts General Hospital; Taylor Savage, Massachusetts General Hospital; Lauren Skirvin, Massachusetts General Hospital; Emma Wolper, Massachusetts General Hospital; and Elizabeth Thiele, Massachusetts General Hospital
Content: Rationale: Patients with severe refractory epilepsy were treated with open-label, purified 98% cannabidiol (CBD) extract (Epidiolex, GW Pharmaceuticals) through the Pediatric Epilepsy Program at Massachusetts General Hospital.  The effect of CBD treatment on seizure frequency in those treated with clobazam vs. those not treated with clobazam was evaluated. The relationship with norclobazam levels, the active metabolite of clobazam, and change in seizure frequency with concomitant CBD use was also investigated. Methods: Fifty-six patients with severe refractory epilepsy participated in an expanded access IND program with purified 98% CBD extract. Seizure types included tonic, tonic-clonic, atonic, myoclonic, absence, focal dyscognitive, and epileptic spasms. Thirty-five patients were on concomitant treatment with clobazam during the entire first year of treatment with CBD. Fifteen patients were not taking clobazam during this time frame. Three patients were started on clobazam after commencing treatment with CBD, 2 were taken off clobazam due to severe drowsiness, a presumed interaction with CBD, and 1 patient died from unrelated factors.Demographic information and epilepsy history were collected for all patients.  After a one month baseline period, patients were started on CBD at dosage 5 mg/kg/daily, increasing in increments of 5 mg/kg/day, as tolerated, to a maximum dosage of 50 mg/kg/day. Seizure frequency was recorded and used to evaluate responder rates during the first year of treatment with CBD. A responder was defined as a patient with greater than 50% reduction of seizures from their baseline frequency at their lowest seizure frequency during their first year. For those patients taking clobazam, clobazam dose and clobazam and norclobazam levels were recorded. Side effects of treatment as well as parental reports of subjective cognitive and behavioral changes were noted.  Results: The 35 patients treated with CBD and clobazam had a 59% average reduction in seizure frequency. Twenty-five of the 35 patients (71.4%) were considered responders, with an 80.4% average reduction in seizure frequency. The 15 patients treated without concomitant clobazam had a 49.5% average reduction in seizure frequency.  Five of the 15 patients (33.3%) were considered responders, with an 87.8% average reduction in seizure frequency.All of the patients treated without concomitant clobazam experienced a reduction in seizure frequency. However, 14.29% (5) of the patients treated with both CBD and clobazam experienced an increase in seizures. All of the patients treated with concomitant clobazam also had their clobazam dose reduced due to drowsiness, a recognized interaction with CBD, at some point during their first year of treatment.The norclobazam levels for the patients treated with both CBD and clobazam were 2.4 times higher than at baseline. The norclobazam levels of the responders in this group were 2.56 times higher than at baseline. However, there was no significant correlation between norclobazam level and seizure frequency (-0.31). Conclusions: The data suggests that CBD without concomitant clobazam can be effective in reducing seizure frequency. Concomitant use of clobazam and CBD seems to yield a greater reduction in seizure frequency for patients with refractory epilepsy.Results suggest that the elevated norclobazam levels associated with concomitant use of CBD and clobazam do not have a strong relationship to seizure reduction.  Funding: none