IP 110. Maintenance of Long-Term Safety and Efficacy of Cannabidiol Treatment in Dravet’s Syndrome: Results of an Open-Label Extension Trial (GWPCARE5)

Background: Cannabidiol (CBD) significantly reduced seizures associated with Dravet’s syndrome (DS) and was generally well tolerated in the randomized controlled trial GWPCARE1. We present a prespecified interim analysis of an open-label extension (OLE) trial (GWPCARE5; NCT02224573).

Aims: This OLE trial was designed to assess the long-term safety and efficacy of CBD as an add-on to existing antiepileptic drug (AED) treatment in patients with treatment-resistant DS.

Question: Is the CBD treatment effect and safety profile observed in previous placebo-controlled trials in DS maintained with long-term treatment?

Methods: Children and adults who had previously participated in a 14-week, double-blind, randomized, controlled DS trial (GWPCARE1; NCT02091375 or GWPCARE2; NCT02224703) could enroll into the OLE and be treated for up to 2 years with a plant-derived pharmaceutical formulation of CBD (100 mg/mL) in an oral solution. Initially, patients were titrated to 20 mg/kg/d, which could then be decreased or increased up to 30 mg/kg/d at the investigator’s discretion. The primary end point was safety with key secondary end points of convulsive and total seizure frequency, and the subject/caregiver global impression of change (S/CGIC). This is the first planned interim analysis to support regulatory submissions with a cutoff date, November 3, 2016. As GWPCARE2 is ongoing and still blinded, original baseline data or data expressed as a percentage of original baseline include patients from GWPCARE1 only.

Results: A total of 264 patients with DS enrolled from GWPCARE1 and GWPCARE2; at the time of analysis, 75 had withdrawn, including 17 for adverse events (AEs). Patients were aged 2.5 to 19.3 years; mean age 9.8 years and 50% male. Patients were taking a median of 3 concomitant AEDs (clobazam 68%; valproic acid 64%). Mean (min–max) modal dose for the treatment phase was 21 (2.5–30) mg/kg/d. Patients were exposed for a median of 274 days (range: 1–512 days). AEs occurred in 93% of patients and were considered treatment related by the investigator(s) in 64%. Of patients reporting an AE, 81% reported it as mild or moderate severity. AEs occurring in ≥10% of patients were diarrhea, pyrexia, decreased appetite, somnolence, nasopharyngitis, convulsion, vomiting, upper respiratory tract infection, status epilepticus, and fatigue. Some elevations in transaminases were reported. Serious AEs were reported in 29% of patients and were considered treatment related in 8%. There were two deaths; neither was deemed treatment related. In patients with baseline data, median monthly convulsive seizures decreased by (min–max) 38 to 44% from 12.4 at baseline and median monthly total seizures decreased by (min–max) 39 to 51% from 32.4 at baseline when analyzed over four 12-week periods. An improvement in overall condition on the S/CGIC was reported by 82 and 85% of patients/caregivers at weeks 24 and 48, respectively.

Conclusion: Long-term add-on CBD treatment continued to be generally well tolerated with a similar AE profile to that observed in previous controlled trials of CBD in DS. Results showed a reduction in convulsive and total seizure frequency through 48 weeks of exposure with a high proportion of patients/caregivers reporting an improvement in patients’ overall condition.

Funding: GW Research Ltd.