title: Designing a new proof-of-principle trial for treatment of partial seizures to demonstrate efficacy with minimal sample size and duration-a case study.
abstract: The ideal proof-of-principle study design provides a strong efficacy signal over the shortest duration, while exposing the fewest patients possible. Data from a large database (Pfizer Inc) which studied add-on pregabalin for the treatment of partial seizures was used to model how duration of baseline, post-randomization treatment period, and number of subjects impact the likelihood of an interpretable efficacy signal. Data from four double-blind, randomized, placebo-controlled, phase III studies that had at least one 600 mg/day treatment arm were combined. The common 6-week baseline period was divided into weekly intervals, as was the 12-week post-randomization period. Two methods of analysis were used: logistic regression performed on 50% responder rate and the Hodges-Lehmann estimate on percentage reduction from baseline seizure rate. A simulation-based re-sampling approach was used to determine sufficient sample size. Four weeks of baseline with 3 weeks of treatment were determined to be clinically and statistically sufficient. A reasonable sample size was estimated to be 40-50 patients per group, if a highly efficacious drug was used. These modeling results indicate that the efficacy of an antiepileptic drug can be demonstrated in a relatively short period of time with a reasonable sample size.
authors.affiliation: NYU Comprehensive Epilepsy Center, Department of Neurology, New York University, 223 East 34th Street, New York, NY 10016, USA. Jacqueline.French@nyumc.org
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: French
authors.forename: Javier
authors.initials: J
authors.lastname: Cabrera
authors.forename: Birol
authors.initials: B
authors.lastname: Emir
authors.forename: Ed
authors.initials: E
authors.lastname: Whalen
authors.forename: Feihan
authors.initials: F
authors.lastname: Lu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D016208:Databases, Factual; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D000069583:Pregabalin; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D018401:Sample Size; D012640:Seizures / Q000517:prevention & control; D016896:Treatment Outcome; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid
keywords: AED; Anticonvulsant; Antiepileptic; CI; Epilepsy; HLE; Hodges–Lehmann estimate; OR; PoP; Pregabalin; Proof-of-principle; SD; antiepileptic drug; confidence interval; odds ratio; proof-of-principle; standard deviation