Annual Meeting Abstracts: View
(Abst. 3.278), 2017
A phase-2 study of pharmaceutical grade synthetic cannabidiol oral solution for treatment of refractory infantile spasms
Authors: Shaun A. Hussain, David Geffen School of Medicine at UCLA; UCLA Mattel Children’s Hospital; Dennis J. Dlugos, The Children's Hospital of Philadelphia and Perelman School of Medicine; Maria Roberta Cilio, University of California, San Francisco; D. Alexander Oh, INSYS Development Company, Inc.; Neha Parikh, INSYS Development Company, Inc.; and Raman Sankar, David Geffen School of Medicine at UCLA; UCLA Mattel Children’s Hospital
Content: Rationale: Limited data (Hussain et al 2015) suggest that cannabidiol (CBD) may be effective for treatment of infantile spasms (IS), including refractory cases. This study was designed to more rigorously evaluate the efficacy of synthetic CBD in the treatment of IS. Methods: We recruited children ages 6 to 36 mo with IS who had failed therapy with both ACTH and vigabatrin. We excluded children receiving clobazam, felbamate, or the ketogenic diet, as well as children with any cannabinoid exposure in the prior month. All patients underwent baseline overnight video-EEG (VEEG) to confirm spasms and determine burden of hypsarrhythmia. Patients were treated with pharmaceutical grade synthetic cannabidiol oral solution (COS, Insys Development Company, Chandler AZ) at a dose of 20 mg/kg/day divided BID. After 14 days of treatment, patients returned for repeat overnight VEEG to evaluate response, and tabulate any adverse event (AE). VEEG studies were completely de-identified and reviewed in a pairwise fashion (pre- and post-treatment) by an external, blinded electroencephalographer (DJD). The primary endpoint was freedom from spasms and hypsarrhythmia on day 14. Results: We enrolled 9 patients (median age, 23 mo) with long duration of IS and multiple treatment failures (see Table). Pt #5 was classified as a responder. Baseline IS burden was reported as 2-3 clusters/day with 40 spasms per cluster, and confirmed on baseline video-EEG. The patient’s parent reported no spasms on days 1-5 of COS treatment, a single cluster on day 6, and no further spasms on days 7 through 14. Absence of spasms and hypsarrhythmia was confirmed on day 14 VEEG. Although parent-reported IS relapse occurred on day 18, the burden of spasms never returned to baseline. At most recent follow-up, she continues to receive CBD in a long-term safety study, and is 4-weeks seizure-free on a combination of CBD (40 mg/kg/d), vigabatrin, and topiramate. In contrast, 8 patients exhibited neither clinical nor electrographic response. There were 5 subjects with at least 1 AE, and all were classified as mild. Of note, pt #7 withdrew from the study after 5 days to pursue other treatment. With respect to pharmacokinetics, there was no significant association between response and day 14 serum concentrations of CBD and 7-OH-CBD. The dose-normalized trough concentration of CBD ranged from 3 to 5 ng/mL/mg/kg across all visits. Conclusions: The immediate response in a single patient suggests that CBD may be effective in the treatment of refractory IS. However, we cannot exclude the possibility that response in a single patient represents a spontaneous or transient change in IS burden, unrelated to CBD. Further study, examining both short- and long-term outcomes is warranted to evaluate the efficacy and safety of CBD in the treatment of IS, ideally in a larger and less refractory population. Funding: This study was sponsored by Insys Development Company (Chandler, AZ).