Factors associated with placebo response rate in randomized controlled trials of antiseizure medications for focal epilepsy
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.454 | 0.539 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.005 | 0.014 |
| Bibliometrics | 0.003 | 0.006 |
| Science and technology studies | 0.001 | 0.004 |
| Scholarly communication | 0.004 | 0.004 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.004 | 0.004 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; the direct Gemma label and the distilled Codex classifier agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".