Abstracts

Rationale: Antiepileptic drug (AED) therapy with third-generation AEDs, such as eslicarbazepine acetate (ESL), is used to treat focal seizures (FS). The safety and efficacy of adjunctive ESL were studied in a randomized Phase 3 global clinical trial (ClinicalTrials.gov NCT00988429) of patients (>=16 years) with refractory FS that included a baseline period and a 14-week treatment period. The relationship between seizure severity, patient characteristics, and standardized (standardized to a 28-day period) seizure frequency (SSF) has not been assessed for patients treated with ESL. This post hoc analysis examined the associations of change in seizure severity measured by the Seizure Severity Questionnaire (SSQ), with 1) patient baseline characteristics and 2) SSF percent change. Methods: Patients were randomized to placebo (n=226), ESL 800 mg QD (n=216), or ESL 1200 mg QD (n=211). SSF and SSQ were measured at baseline and week 14. SSQ change score and percent change in SSF were calculated at week 14 from baseline. A negative SSQ change indicates reduction in seizure severity. A negative percent change in SSF indicates reduction in seizure frequency. SSF reduction was categorized as: ≥75%, 50% to <75%, 0% to <50%, and no reduction. Linear regression models with backwards elimination (p>0.10) were used to measure the association of SSQ change (total score [TS] and subscale scores) with 1) patient baseline characteristics, controlling for treatment and baseline SSQ and 2) percent change in SSF, while controlling for treatment, baseline SSQ, and patient characteristics. Results: Among the per-protocol population, 547 patients were included in the analysis: 51% were female and median age was 38 years. Only the number of AEDs during baseline remained in the model of patient baseline characteristics associated with SSQ TS change; however, the association was not significant (P=0.0606). For the SSQ During Seizures (DS) subscale, taking 0 to 1 AEDs during baseline was associated with DS change (-0.41, 95% confidence interval [CI]: -0.74,-0.08; P=0.0154) compared to patients taking 2 or more AEDs. Additionally, treatment with ESL 1200 mg compared to placebo was significantly associated with SSQ TS change (-0.51, 95% CI: -0.80,-0.23; P=0.0005), DS change (-0.46, 95% CI: -0.83,-0.08; P=0.0161) After Seizures (AS) change (-0.54, 95% CI: -1.01,-0.07; P=0.0251), and Severity and Bothersomeness (SB) change (-0.55, 95% CI: -0.86,-0.24; P=0.0005) (Figure 1). Treatment with ESL 800 mg was significantly associated with SSQ SB change (-0.38, 95% CI: -0.68,-0.09; P=0.0116) but not with SSQ TS change (P=0.1753). A significant association was observed between SSQ TS change and SSF reduction compared to no reduction: >=75% (-1.44, 95% CI: -1.77,-1.11; P<0.0001); 50% to <75% (-0.49, 95% CI: -0.82,-0.16; P=0.0035); 0% to <50% (-0.35, 95% CI: -0.63,-0.07; P=0.0154) (Figure 2). Similar results were observed for SSQ DS (P<0.0001), AS (P<0.0001), and SB (P<0.0001). Conclusions: These analyses suggest that treatment with ESL was associated with statistically significant improvement in seizure severity. Significant severity reduction was also associated with baseline use of fewer AEDs (0-1 vs. >=2). The analyses further suggest that, on average, patients experiencing greater SSF reduction reported a greater improvement in seizure severity. Further investigation into the relationship between AED treatment, SSF reductions, and improvement in seizure severity is warranted. Funding: Study funding provided by Sunovion Pharmaceuticals Inc.