Abstracts

Rationale: Clinical trials of new treatments in epilepsy have traditionally been designed and powered to detect a decrease in seizure frequency as the primary endpoint, with little consideration given to other benefits or harms of the therapy, including impacts on common epilepsy comorbidities or overall quality of life. In collaboration with a consumer group of people with epilepsy, we adapted the desirability of outcome ranking (DOOR) for use as a primary endpoint for therapeutic clinical trials for epilepsy.¹ This study aimed to validate the Epilepsy-DOOR using existing clinical trial data, comparing its sensitivity and power to standard outcome measures for treatment trials in epilepsy.

Methods: The Epilepsy-DOOR includes 60 levels of desirability of outcome, combining change in seizure frequency, adverse events and change in quality of life, thus providing a multifaceted assessment of the benefits and harms of the treatment being trailed. Data from three phase 3 double blind randomised controlled trials of brivaracetam ([BRV] N01252, N01253 and N01254) were used to evaluate the sensitivity of Epilepsy-DOOR for detecting benefit of treatment over placebo (PCB) in comparison to responder rate and absolute change in seizure frequency. Group sizes in each trial ranged from 90-100 participants treated with one of 3 brivaracetam doses or placebo. The Epilepsy-DOOR was calculated for each participant over the main double blind study period (12 or 16 weeks: study dependent). Win ratios, the probability that a randomly chosen participant in the treatment group will have a better outcome than a randomly chosen participant in the placebo group, were calculated between groups for the epilepsy-DOOR. A win ratio >1 demonstrates benefit of the treatment. Conversion to effect sizes allowed direct comparison with responder rate and change in seizure frequency.


Results: In N01252, the epilepsy DOOR showed similar effect size (1.42, 95% CI 1.03, 1,97, p=0.03) to seizure frequency (1.47, 95% CI 1.10,1.97, p=0.01), both showing benefit of the highest dose of BRV (100mg daily) over PCB (Figure 1). Interestingly the lowest dose (20mg daily) trended to benefit of treatment (1.32, 95% CI 0.96, 1.84, p=0.09) but the middle dose (50mg daily) did not (1.01, 95% CI 0.73, 1.4, p=0.93). Similar results were observed in N01253, where the highest dose of BRV (50mg daily) showed benefit on seizure frequency (1.58, 95% CI 1.18, 2.11, p< 0.01), but the DOOR did not attain significance (1.28, 95% CI 0.92, 1.77, p=0.14). The lesser benefit on the Epilepsy-DOOR reflected reductions in seizures being counterbalanced by worse adverse events. Epilepsy-DOOR did not demonstrate any benefit of BRV (flexible dosing) over placebo in N01254, despite improvements in seizure frequency.