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Summary   Objective  To determine long‐term safety and efficacy of adjunctive clobazam for patients with  L ennox‐ G astaut syndrome ( LGS ).    Methods  Eligible patients from two randomized controlled trials (Phase  II OV ‐1002 and Phase  III OV ‐1012) were able to enroll in open‐label extension ( OLE ) study  OV ‐1004 beginning in December 2005 and received clobazam until they discontinued (mandatory at 2 years for patients outside the  U nited  S tates) or until study completion in March 2012.  P atients in the United States could have received clobazam for 6 years before it became commercially available. Efficacy assessments included changes in rates of drop seizures and total seizures, responder rates (≥50%, ≥75%, or 100% decreases in seizure frequency vs. baseline), sustained efficacy over time, concomitant antiepileptic drug ( AED ) use, and global evaluations. Safety assessments included exposure to clobazam, laboratory assessments, physical and neurologic examinations, vital sign monitoring, electrocardiography monitoring, and adverse event reporting.    Results  Of 267 patients who enrolled in the  OLE , 188 (70%) completed the trial. Two hundred seven patients were from the  U nited  S tates, which was the only country in which patients could be treated with clobazam for >2 years. Forty‐four patients were treated with clobazam for 5 years, and 11 for 6 years. Because of the low number of Year 6 patients, this group is not reported separately. Improvements in baseline seizure rates were very stable over the course of the study, with a median 85% decrease in drop seizures at Year 1, 87% at Year 2, 92% at Year 3, 97% at Year 4, and a 91% decrease for patients who had reached Year 5. Similar results were observed for total seizures (79% decrease at both Years 1 and 2, 82% decrease at Year 3, 75% decrease at Year 4, and 85% decrease at Year 5). Responder rates were also stable for the duration of the trial. Of patients who had achieved a ≥50% decrease in median drop‐seizure frequency from baseline to Month 3, 86% still had that degree of drop‐seizure reduction at Year 3 (and 14% lost their initial responses), and 47% were drop‐seizure–free. Most patients who had achieved drop‐seizure freedom in the original controlled trials remained drop‐seizure–free in the  OLE . Based on parents' and physicians' ratings of global evaluations, 80% of patients were “very much improved” or “much improved” after 3 years. Of the 43 patients with concomitant  AED  data who were treated for 5 years, 30% increased, 19% decreased, and 51% had no change in numbers of  AED s versus their Week 4 regimens. The mean modal clobazam dosage was 0.90 mg/kg/day at Year 1 and 0.97 mg/kg/day at Year 5, suggesting that study patients did not need significant increases in dosage over time. The safety profile was what would be expected for clobazam for  LGS  patients over a 5‐year span, and no new safety concerns developed over time.    Significance  In this largest and longest‐running trial in  LGS , adjunctive clobazam sustained seizure freedom and substantial seizure improvements at stable dosages through 3 years of therapy in this difficult‐ to‐treat patient population.  A PowerPoint slide summarizing this article is available for download in the Supporting Information section  here .

Stable dosages of clobazam for L ennox‐ G astaut syndrome are associated with sustained drop‐seizure and total‐seizure improvements over 3 years