Alternative Trial Methodology in Pediatric Epilepsy Clinical Trials - Time to “Nth” Seizure Analysis in Children with Partial Onset Seizures Treated With Pregabalin (S53.002)

Objective: To compare alternative planned exploratory time-to-Nth seizure methodology with conventional primary efficacy analyses in children receiving pregabalin as adjunctive treatment for partial onset seizures (POS). Background: In conventional assessments of medication efficacy for POS, subjects remain on study drug or placebo for the entire treatment phase. Time-to-Nth seizure methodologies allow subjects to potentially exit earlier, while still providing evaluable efficacy endpoints. Design/Methods: The double-blind (DB), placebo-controlled, multi-country Study A0081041 (www.clinicialtrials.govNCT01389596) included an 8-week baseline phase (BL) and 12-week DB treatment phase (2-week dose escalation; 10-week fixed dose). Subjects (4–16 years old) with POS received stable regimens of 1–3 antiepileptic drugs. Treatments included pregabalin 2.5mg/kg/day (PGB-2.5; maximum 150mg/day), 10mg/kg/day (PGB-10; maximum 600mg/day), or placebo; doses were adjusted to achieve similar exposure for children weighing e (28-day seizure rates) over DB treatment, using linear mixed models with fixed-effect terms for baseline log e (28-day seizure rate), region, treatment, and weight. The alternative analysis was time-to-Nth seizure during DB treatment, where “Nth seizure” was derived from the 28-day BL seizure rate. Kaplan-Meier survival analysis and log-rank tests evaluated median time-to-Nth seizure and statistical significance, respectively. Results: 294 patients were analyzed (mean age 10.2 years, 55% male; PGB-10 n=97, PGB-2.5 n=104, placebo n=93). In the conventional approach, log e (28-day seizure rates) were reduced (relative to placebo) with PGB-10 (−19.9%, P =0.0185) and PGB-2.5 (−9.9%, P =0.2577). Using the alternative approach and censoring subjects not reaching Nth seizure, PGB-10 subjects reached their Nth seizure in the DB phase later than placebo ( P =0.0036). PGB-2.5 subjects showed a non-significant trend for longer time-to-Nth seizure versus placebo ( P =0.2721). Conclusions: Time-to-Nth seizure was longer for PGB-10 (significantly) and PGB-2.5 (numerically) versus placebo and compared favorably with the conventional analysis suggesting this as a viable trial methodology in pediatrics. Study Supported by: Pfizer Disclosure: Dr. Antinew has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer. Dr. Antinew has received compensation for serving on the Board of Directors of Pfizer. Dr. Knapp has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer. Dr. Knapp has received compensation for serving on the Board of Directors of Pfizer. Dr. Almas has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer. Dr. Liu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer. Dr. Liu has received compensation for serving on the Board of Directors of Pfizer. Dr. Scavone has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer. Dr. Scavone has received compensation for serving on the Board of Directors of Pfizer. Dr. Parsons has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer. Dr. Parsons has received compensation for serving on the Board of Directors of Pfizer.