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(Abst. 3.294), 2018

Long-Term Safety of Pharmaceutical Cannabidiol Oral Solution as Adjunctive Treatment for Pediatric Patients With Treatment-Resistant Epilepsy
Authors: Maria R. Cilio, University of California - San Francisco; James W. Wheless, University of Tennessee, Le Bonheur Children’s Hospital; Dennis Dlugos, Children’s Hospital of Philadelphia; Neha Parikh, INSYS Development Company, Inc.; and Ian Miller, Nicklaus Children's Hospital
Content: Rationale: Cannabidiol (CBD) is the second most abundant cannabinoid in plant cannabis. Unlike ? 9-tetrahydrocannabinol, CBD is not psychoactive. It has demonstrated potential benefit in treating patients with treatment-resistant epilepsy.1,2 Methods: This multicenter, open-label, flexible-dose study assessed long-term safety and tolerability of pharmaceutical grade CBD oral solution as adjunctive treatment for pediatric patients with treatment-resistant epilepsy. Patients who previously completed a CBD oral solution study (multiple-dose pharmacokinetic study or Phase 2 study) were eligible. Patients received the same dose as in the previous study (10, 20, or 40 mg/kg/d in 2 divided doses) for ~48 weeks, with dose changes at investigator discretion. Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms, physical and neurologic exams, and lab tests. Additional assessments included Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I) by investigator and caregiver at baseline (CGI-S only), Week 4, 8, 12, 24, 36, final visit, and follow-up visit. Results: Fifty-two patients (9 infants [aged 1 to <2 years], 26 children [aged 2 to <12 years], and 17 adolescents [aged 12 to =17 years]) were enrolled; 45 (86.5%) completed the study. Mean modal dose was 24.4 mg/kg/d, and was higher in infants than children or adolescents. Mean total duration of study drug was 311.1 days, with maximum exposure 384 days. Overall, 47 patients (90.4%) experienced =1 TEAE; 24 (46.2%) patients had TEAEs that were possibly or probably related to study drug, most mild or moderate in intensity. A majority of the drug-related TEAEs (35 of 47 events) occurred in children. The most common TEAEs (=10% incidence) were seizure, upper respiratory tract infection, somnolence, anemia, diarrhea, and pyrexia. There were 37 serious adverse events (SAEs), 3 of which were considered possibly related to study drug: (1) moderate change in seizure presentation of generalized tonic clonic seizure, as opposed to the usual spasms, resulting in hospitalization, with no action taken with respect to study drug; (2) moderate ataxia resulting in hospitalization, with reduction in study drug dose; (3) worsening seizure exacerbation resulting in hospitalization, with study drug discontinued. Additionally, 2 patients discontinued due to a TEAE (aggression [n=1] and seizure [n=1]). Among the other SAEs that were unrelated to study drug, there was 1 death due to multiorgan failure and sepsis. There were no clinically meaningful changes in other safety assessments. Caregivers and investigators reported modest reductions in CGI-S and improvements in CGI-I from baseline to follow-up visit. Conclusions: Results demonstrated long-term use (up to ~13 months) of CBD oral solution (10-40 mg/kg/d) was generally safe and well tolerated.ReferencesThiele EA, et al. Lancet. 2018;391(10125):1085-1096.Devinsky O, et al. N Engl J Med. 2017;376(21):2011-2020. Funding: Insys Development Company, Inc.