Difference in background factors between responders to gabapentin enacarbil treatment and responders to placebo: pooled analyses of two randomized, double-blind, placebo-controlled studies in Japanese patients with restless legs syndrome

Objective: Restless legs syndrome (RLS) is a sensorimotor disorder that is characterized by uncomfortable and unpleasant sensations mainly in the legs. Two placebo-controlled studies (Phase II/III and post-marketing) in Japanese patients with RLS failed to demonstrate the efficacy of gabapentin enacarbil (GE) 600 mg in the change from baseline in International Restless Legs Syndrome Rating Scale (IRLS) score at the end of the treatment period. The high response to placebo is thought to be a possible reason why the post-marketing study failed. The objectives of these post hoc analyses were to determine potential predictive factors associated with improvement in IRLS score with GE treatment and to identify subgroups with higher placebo responses. Methods: We combined data from the two Japanese studies and analyzed change from baseline in IRLS score in the pooled population and subgroups defined by several patient characteristics. Moreover, we calculated the variable importance of each factor and performed predictive enrichment analysis to identify an enrichable subpopulation with greater improvement by GE treatment. Results: The post hoc analyses suggested that higher baseline IRLS score (>= 21) and higher body mass index (>= 25 kg/m(2)) were associated with higher placebo responses. On the other hand, positive family history of RLS, prior use of dopaminergic receptor agonists, and higher baseline ferritin level (>= 50 ng/mL) were associated with higher responses to GE. Conclusions: Our results suggest that patients with typical idiopathic RLS characteristics, including positive family history and no low ferritin level, would be expected to derive the greatest benefits from GE treatment. (C) 2021 The Authors. Published by Elsevier B.V.