Factors associated with placebo response rate in randomized controlled trials of antiseizure medications for focal epilepsy

Abstract

Objective: Randomized controlled trials (RCTs) are necessary to evaluate the efficacy of novel treatments for epilepsy. However, there have been concerning increases in the placebo responder rate over time. To understand these trends, we evaluated features associated with increased placebo responder rate.

Methods: Using individual-level data from 20 focal-onset seizure trials provided by seven pharmaceutical companies, we evaluated associations with change in seizure frequency in participants randomized to placebo. We used multivariable logistic regression to evaluate participant and study factors associated with differing rates of 50% reduction in seizure frequency during blinded placebo treatment, as compared to pre-randomization baseline seizure frequency. In addition, we focused on the association of placebo responder rate with pre-randomization baseline seizure frequency and country of recruitment.

Results: In the pooled analysis of 1674 participants randomized to placebo, a higher 50% responder rate (50RR) was associated with a shorter duration of epilepsy (p = .006), lower baseline seizure rate (p = .002), fewer concomitant antiseizure medications (p = .004), absence of adverse events (p < .001), more trial arms (p = .006), and geographic region (p < .001). Mixture modeling indicated a significantly higher 50RR in Bulgaria, Croatia, India, and Canada (42% in the higher group vs 22% in the lower group comprising all 40 other countries, p < 10^-15). In addition, there was a significantly higher 50RR in participants with a baseline seizure frequency of six or fewer seizures per 28 days (29% vs 21%, p = .00018).

Significance: These results can assist future RCTs in estimating the expected placebo responder rate, which may lead to more reliable power estimates. Higher placebo responder rate was associated with markers of less-refractory epilepsy. There were concerning significant differences in placebo responder rate by country and geographic region as well as an elevated placebo responder rate in participants with baseline seizure frequency close to the minimum eligibility criteria.

Keywords: clinical trials; epilepsy; nocebo; variability.

FIGURE 1

Multivariable logistic regression demonstrating characteristics associated with placebo 50% responder rate (50RR, *p < .05). For all characteristics in the regression, refer to Figure S1.

FIGURE 2

Differences in placebo 50% responder rate (50RR) based on country of recruitment. Countries with average (reference) 50RR are in gray. Countries with higher 50RR are shades of red, whereas countries with lower 50RR are in shades of blue. Countries other than those highlighted (Bulgaria, Croatia, Canada, and India) with high 50RR recruited insufficient participants to detect a significant difference from the average country (see Table S3). Countries with no participants were not visualized (e.g., most African nations).

FIGURE 3

Placebo 50% responder rate (50RR) associated with baseline seizure frequency. Dashed vertical bar indicates that 50RR was higher in participants with six or fewer baseline seizures per 28 days compared to more than six (p = .00018). Shading reflects binomial exact standard error equivalents with Gaussian smoothing of log baseline seizure frequency with standard deviation of 1.3 seizures per 28 days.