Quantifying and controlling the impact of regression to the mean on randomized controlled trials in epilepsy.

OBJECTIVE: Randomized controlled trials (RCTs) in epilepsy for drug treatments are plagued by high costs. One potential remedy is to reduce placebo response via better control over regression to the mean (RTM). Here, RTM represents an initial observed seizure rate higher than the long-term average, which gradually settles closer to the average, resulting in apparent response to treatment. This study used simulation to clarify the relationship between eligibility criteria and RTM.

METHODS: Using a statistically realistic seizure diary simulator, the impact of RTM on placebo response and trial efficacy was explored by varying eligibility criteria for a traditional treatment phase II/III RCT for drug-resistant epilepsy.

RESULTS: When the baseline period was included in the eligibility criteria, increasingly larger fractions of RTM were observed (25%-47% vs. 23%-25%). Higher fractions of RTM corresponded with higher expected placebo responses (50% responder rate [RR50]: 2%-9% vs. 0%-8%) and lower statistical efficacy (RR50: 47%-67% vs. 47%-81%). The exclusion of baseline from eligibility criteria was shown to decrease the number of patients needed by roughly 30%.

SIGNIFICANCE: The manipulation of eligibility criteria for RCTs has a predictable and important impact on RTM, and therefore on placebo response; the difference between drug and placebo was more easily detected. This in turn impacts trial efficacy and therefore cost. This study found dramatic improvements in efficacy and cost when baseline was not included in eligibility.