title: Impact of responder definition on the enriched enrollment randomized withdrawal trial design for establishing proof of concept in neuropathic pain.
abstract: 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 neuropathic pain. Adults with moderate to severe peripheral neuropathic pain entered a 3- to 4-day screening period, followed by a 12-day titration to the highest tolerated dose that provided pain 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 pain intensity and were randomized to placebo or pregabalin during the randomized withdrawal period. The primary endpoint was mean of average 24-h pain 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. Pregabalin-treated subjects (n=52) had significantly less pain 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 painful diabetic neuropathy. The EERW trial design using time-to-efficacy-failure may provide a sensitive and efficient method to conduct POC studies of novel therapies in patients with neuropathic pain. Enriching a study population with patients who have achieved a 30% decrease in pain 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 neuropathic pain.
authors.affiliation: Merck Research Laboratories, White house Station, NJ, USA Nuvo Research Inc., West Chester, PA, USA University of Wisconsin-Madison, WI, USA Mood & Anxiety Research, Inc., Fresno, CA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hewitt
authors.forename: Tony W
authors.initials: TW
authors.lastname: Ho
authors.forename: Bradley
authors.initials: B
authors.lastname: Galer
authors.forename: Miroslav
authors.initials: M
authors.lastname: Backonja
authors.forename: Paul
authors.initials: P
authors.lastname: Markovitz
authors.forename: Arnold
authors.initials: A
authors.lastname: Gammaitoni
authors.forename: David
authors.initials: D
authors.lastname: Michelson
authors.forename: James
authors.initials: J
authors.lastname: Bolognese
authors.forename: Achilles
authors.initials: A
authors.lastname: Alon
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rosenberg
authors.forename: Gary
authors.initials: G
authors.lastname: Herman
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000704:Analysis of Variance; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000188:drug therapy* / Q000401:mortality; D010147:Pain Measurement; D000069583:Pregabalin; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000700:Analgesics; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid