Does accounting for seizure frequency variability increase clinical trial power?

Journal Article (Journal Article)

OBJECTIVE: Seizure frequency variability is associated with placebo responses in randomized controlled trials (RCT). Increased variability can result in drug misclassification and, hence, decreased statistical power. We investigated a new method that directly incorporated variability into RCT analysis, ZV. METHODS: Two models were assessed: the traditional 50%-responder rate (RR50), and the variability-corrected score, ZV. Each predicted seizure frequency upper and lower limits using prior seizures. Accuracy was defined as percentage of time-intervals when the observed seizure frequencies were within the predicted limits. First, we tested the ZV method on three datasets (SeizureTracker: n=3016, Human Epilepsy Project: n=107, and NeuroVista: n=15). An additional independent SeizureTracker validation dataset was used to generate a set of 200 simulated trials each for 5 different sample sizes (total N=100 to 500 by 100), assuming 20% dropout and 30% drug efficacy. "Power" was determined as the percentage of trials successfully distinguishing placebo from drug (p<0.05). RESULTS: Prediction accuracy across datasets was, ZV: 91-100%, RR50: 42-80%. Simulated RCT ZV analysis achieved >90% power at N=100 per arm while RR50 required N=200 per arm. SIGNIFICANCE: ZV may increase the statistical power of an RCT relative to the traditional RR50.

Full Text

Duke Authors

Cited Authors

  • Goldenholz, DM; Goldenholz, SR; Moss, R; French, J; Lowenstein, D; Kuzniecky, R; Haut, S; Cristofaro, S; Detyniecki, K; Hixson, J; Karoly, P; Cook, M; Strashny, A; Theodore, WH; Pieper, C

Published Date

  • November 2017

Published In

Volume / Issue

  • 137 /

Start / End Page

  • 145 - 151

PubMed ID

  • 28781216

Pubmed Central ID

  • PMC5650933

Electronic International Standard Serial Number (EISSN)

  • 1872-6844

Digital Object Identifier (DOI)

  • 10.1016/j.eplepsyres.2017.07.013


  • eng

Conference Location

  • Netherlands