Impact of responder definition on the enriched enrollment randomized withdrawal trial design for establishing proof of concept in XXXX .

@entity1 @entity3949 @entity158 @entity4481 @entity9
The objective of this study was to evaluate how enrichment for responders increases assay sensitivity in an enriched enrollment randomized withdrawal (EERW) proof-of-concept (POC) study in @entity9 . Adults with moderate to severe peripheral @entity9 entered a 3- to 4-day screening period, followed by a 12-day titration to the highest tolerated dose that provided @entity158 control (pregabalin 50-200mg t.i.d.), and then a 9-day maintenance period. Subjects were stratified as primary responders (   30%), secondary responders (   10% to <30%), or nonresponders (<10%) based on decrease in @entity158 intensity and were randomized to placebo or @entity4481 during the randomized withdrawal period. The primary endpoint was mean of average 24-h @entity158 intensity during the last 3days of treatment period relative to the 3days before randomization. Time-to-efficacy-failure was the key secondary endpoint. Other features included not requiring discontinuation of current analgesic therapies and blinding investigators to study design elements that could contribute to non-treatment-related responses. Effect size (ES) (mean treatment difference/SD) was used to measure assay sensitivity. @entity4481 -treated subjects (n=52) had significantly less @entity158 than those receiving placebo (n=51) (P   .003). Effect size of the primary endpoint was 0.72 for primary responders and decreased if secondary and nonresponders were included in the analysis. The highest ES (1.68) was demonstrated for the endpoint time-to-efficacy-failure seen in primary responders with @entity3949 . The EERW trial design using time-to-efficacy-failure may provide a sensitive and efficient method to conduct POC studies of novel therapies in @entity1 with @entity9 . Enriching a study population with @entity1 who have achieved a 30% decrease in @entity158 with an investigational therapy, and using time-to-efficacy-failure during the randomized withdrawal phase as the primary endpoint, can be used for a proof-of-concept study to optimize assay sensitivity and efficiently determine the analgesic potential of a new treatment for @entity9 .
