Does accounting for seizure frequency variability increase clinical trial power?

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, Z_V. Methods Two models were assessed: the traditional 50%-responder rate (RR50), and the variability-corrected score, Z_V. 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 Z_V 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, Z_V: 91–100%, RR50: 42–80%. Simulated RCT Z_V analysis achieved >90% power at N = 100 per arm while RR50 required N = 200 per arm. Significance Z_V may increase the statistical power of an RCT relative to the traditional RR50.