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(Abst. 2.271), 2017

Maintained Safety and Efficacy of Cannabidiol (CBD) in a Long-Term Open-Label Trial in Patients with Lennox-Gastaut Syndrome (LGS) (GWPCARE 5)
Authors: Eric D. Marsh, The Children’s Hospital of Philadelphia; Maria Mazurkiewicz-Beldzinska, Medical University of Gdansk; Jonathan J. Halford, Medical University of South Carolina; Boudewjin Gunning, SEIN – Stichting Epilepsie Instellingen Nederland, Zwolle, Netherlands.; Daniel Checketts, GW Research Ltd; Kathryn Nichol, Greenwich Biosciences; and Elizabeth Thiele, Massachusetts General Hospital
Content: Rationale: LGS is a rare epileptic encephalopathy that is often treatment resistant. The efficacy and safety of CBD in the treatment of seizures associated with LGS has previously been demonstrated in the phase 3 controlled GWPCARE 3 (NCT02224560) and GWPCARE 4 (NCT02224690) trials. Here we present a pre-specified interim analysis of the open-label extension (OLE) of these trials designed to assess the long-term safety and efficacy of add-on CBD to existing antiepileptic drug (AED) treatment in children and adults with LGS. Methods: Patients who completed either of the two 14-week (wk), double-blind, randomized controlled trials could enter this OLE study (NCT02224573), in which they received a plant-derived pharmaceutical formulation of CBD (100 mg/mL) in oral solution for up to 2 years (y). Initially, patients were titrated to 20 mg/kg/day (d), which could then be either decreased or increased to 30 mg/kg/d at the investigator’s discretion. The primary endpoint was safety with secondary endpoints of drop-seizure and total-seizure frequency, and the Subject/Caregiver Global Impression of Change (S/CGIC). This is the first of two planned interim analyses to support regulatory submissions, with a cut-off date 03Nov2016. Results: Of the 368 LGS patients who completed GWPCARE 3 or 4, 366 (99%) patients enrolled in the OLE and 67 had withdrawn as of the interim analysis cutoff date. The mean age was 16 y, with 33% ≥18 y, and 54% male. Patients were taking a median of 3 concomitant AEDs (51% clobazam; 37% valproic acid). At pre-randomization baseline, patients had a median of 80 drop seizures and 168 total seizures per 28 d. Mean modal dose for the treatment phase was 23 mg/kg/d (min 2.5, max 30; n=364). Patients were exposed for a mean of 36 wks (range 3 d to 61 wks). Adverse events (AEs) occurred in 92% of patients and were considered treatment-related in 58%; of patients reporting an AE, 83% reported it as mild or moderate severity. AEs occurring in ≥10% of patients were diarrhea, somnolence, convulsion, pyrexia, decreased appetite, vomiting, and upper respiratory tract infection. Some elevations in transaminases were reported. Serious AEs were reported in 26% of patients and were considered treatment-related in 6%. There were 4 deaths; none were deemed treatment-related. When analyzed in 12-wk intervals over 60 wks, median monthly drop seizures decreased by 48%–70%, and total seizures decreased by 48%–62% (Table 1). Approximately 88% of patients/caregivers reported an improvement in overall condition on the S/CGIC at Weeks 24 and 48 (Table 2). Conclusions: Long-term treatment with add-on CBD was generally well tolerated, with a similar AE profile to that observed in the pivotal GWPCARE 3 and 4 trials. CBD resulted in a maintained reduction in both drop and total seizure frequency through 60 wks of exposure, with a high proportion of patients/ caregivers reporting an improvement in overall condition. Funding: GW Research Ltd
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