Abstracts

Rationale: BRV is in development as adjunctive therapy for epilepsy. IV BRV is an alternative to oral therapy when oral administration is not feasible. We present safety/tolerability of IV BRV administered as infusion or bolus.Methods: This open-label, 4-arm, randomized, parallel-group study enrolled patients 16 70yrs ( 18 Germany; 18 65 Czech Republic) with focal or generalized epilepsy uncontrolled on 1 2 concomitant AEDs. Patients were randomized 1:1:1:1 to placebo (PBO) tablets/BRV bolus; PBO tablets/BRV infusion; BRV tablets/BRV bolus; BRV tablets/BRV infusion (Fig 1). The study comprised: 7-day baseline; 7-day double-blind run-in (BRV 200mg/day; PBO tablets [bid]); 4.5-day evaluation (IV BRV 200mg/day [bid]; bolus [2mins] or infusion [15mins], total 9 doses). Completers were down-titrated or switched to a long-term follow-up (LTFU) study. Safety variables were adverse events (AEs), electrocardiograms (ECGs), vital signs, lab assessments. BRV plasma levels were measured at start/end of evaluation period pre/post-dose. Efficacy was not assessed.Results: 105 patients (mean age 41.6 12.2yrs; 53.3% female; 75.2% focal epilepsy) were randomized. 2 patients discontinued due to AEs; 1 PBO/BRV bolus (run-in period, PBO rash); 1 PBO/BRV infusion (evaluation period; anxiety).103 patients completed; 91/105 (86.7%) patients entered LTFU. During the overall study (run-in+evaluation), 76.2% patients reported a treatment-emergent AE (TEAE); 63.8% patients reported drug-related TEAEs. Incidences of TEAEs/drug-related TEAEs were similar across the 4 groups. No deaths or treatment-emergent serious AEs (SAEs) were reported. 3 pre-treatment SAEs were reported by 1 patient (all due to physical assault). During the evaluation period, incidences of TEAEs for IV BRV (bolus+infusion combined) were similar for those who previously received oral PBO (70.6%) or BRV (66.0%) (Table 1). 71.2% patients in BRV bolus arm reported TEAEs vs 65.4% in BRV infusion arm. The most common TEAEs were somnolence and dizziness. Incidence of IV-related TEAEs was low and similar in bolus (9.6%) and infusion (11.5%) groups. Injection site erythema and pain (3.8% each) and infusion site pain (5.8%) were the most common IV-related TEAEs in bolus and infusion groups, respectively. Severe TEAEs were reported by 1 patient (BRV/BRV bolus; vertigo, nausea). No clinically meaningful changes in vital signs, ECGs or lab assessments were seen. At the start of the evaluation period, post-dose BRV plasma concentrations ( g/mL; geometric mean) were 83 88% higher in those who received BRV as opposed to PBO during run-in, but were similar across all groups (PBO/BRV: bolus 3.4, infusion 3.3; BRV/BRV: bolus 3.3, infusion 2.9ug/mL) by end of evaluation period.Conclusions: IV BRV (200mg/day) was similarly well-tolerated when given by bolus or infusion, whether administered de-novo or as conversion from BRV tablets. No new safety concerns were raised. At the end of the evaluation period similar plasma concentrations were seen in patients who received IV BRV as either bolus/infusion. UCB-sponsored