Abstracts

Rationale: Monotherapy is recommended for patients with new onset epilepsy. For an antiepileptic drug to obtain monotherapy approval in Europe, it is required to demonstrate non-inferiority to an established comparator at optimal use. The efficacy and tolerability of pregabalin (PGB) monotherapy was compared with lamotrigine (LTG) using this approach.Methods: Patients ?16 years of age with newly diagnosed partial seizures were enrolled, randomized, and titrated to either double-blind PGB 75 mg or LTG 50 mg twice daily. In compliance with European agency requirements, patients were then followed for 52 weeks in an efficacy assessment phase during which the daily dose could be increased as needed to a maximum of 600 mg PGB or 500 mg LTG. The primary efficacy endpoint was the proportion of patients who remained seizure free for ?6 continuous months during the efficacy assessment phase. In compliance with ILAE guidelines, sample size calculation was based on an absolute non-inferiority margin of -0.10 (relative margin -0.17) in favour of LTG assuming that the true proportion for LTG was 0.60.Results: 660 patients (PGB 330, LTG 330) were randomized, of whom 622 entered the efficacy assessment phase (PGB 314, lamotrigine 308). Treatments were maintained at the lower doses in most patients (Figure). Fewer patients in the PGB group became seizure free for ?6 continuous months than in the LTG group (51.6% vs. 67.9%; difference in proportion, 0.16; 95% confidence interval 0.24 to 0.09) (Table). Post-hoc analyses showed that the difference was clinically significant in patients with only secondary generalised tonic-clonic (SGTC) seizures prior to randomisation (79/139, 56.8% vs 108/135, 80.0%; difference in proportions, 0.232; 95% CI 0.336 to 0.124; nominal p<0.0001) but not in other patients. Time to withdrawal due to lack of efficacy, time to first seizure, and time to 6-month seizure freedom were less favourable in the PGB group. The incidence of adverse events among treatment groups was similar and consistent with product labelling.Conclusions: Results of the present study showed PGB to be inferior to LTG as monotherapy for newly diagnosed partial seizures. However, a substantial proportion of patients remained on their initial starting dose (150 mg PGB and 100 mg LTG) until the end of study. Because efficacy assessment was restricted to 52 weeks, serial dose adjustments based on seizure outcomes made after week 24 would not allow sufficient time in the study to achieve 6 month seizure freedom. Examination of these factors led to our hypothesis that the trial design may have not ensured adequate or equivalent dosing levels between the drugs, particularly with regard to the efficacy of PGB against SGTC seizures. These results highlight potentially important issues, including dose selection/optimization regimens, efficacy assessment schedules, and dose escalation criteria which must be carefully considered for future non-inferiority monotherapy studies in newly diagnosed epilepsy. This study (NCT00280059) was sponsored by Pfizer Inc.