Arbaclofen extended-release tablets for spasticity in multiple sclerosis: Randomized, controlled clinical trial

Abstract

Baclofen, a racemic GABA-B (GABAB) receptor agonist, is commonly used for the management of multiple sclerosis-related spasticity but is associated with frequent dosing and poor tolerability. Arbaclofen, the active R-enantiomer of baclofen, exhibits 100- to 1000-fold greater specificity for the GABAB receptor compared with the S-enantiomer and ∼5-fold greater potency compared with racemic baclofen. Arbaclofen extended-release tablets have a dosing interval of 12 hours and have shown a favourable safety and efficacy profile in early-phase clinical development. The current Phase 3 study was designed to evaluate the efficacy and safety of arbaclofen extended-release tablets in patients with multiple sclerosis-related spasticity. In this multicentre, double-blind, placebo-controlled study, adults with multiple sclerosis-related spasticity were randomized to arbaclofen extended-release 40 mg/day, arbaclofen extended-release 80 mg/day or placebo for 12 weeks. The co-primary end-points were the change from baseline to Week 12 in the Total Numeric-transformed Modified Ashworth Scale in the Most Affected Limb score and the Clinical Global Impression of Change score. A hierarchical testing procedure was used to evaluate the co-primary end-points; analyses for the 80 mg/day group were considered inferential only if the arbaclofen extended-release 40 mg/day and placebo groups demonstrated a statistically significant difference (P ≤ 0.05) for both end-points. Five hundred thirty-six patients were included in the study. At Week 12, the least squares mean change from baseline in Total Numeric-transformed Modified Ashworth Scale in the Most Affected Limb score was -1.67 (95% confidence interval: -1.97 to -1.36) and -1.28 (95% confidence interval: -1.57 to -0.99) in the arbaclofen extended-release 40 mg/day and placebo groups, respectively (least squares mean difference: -0.39; P < 0.048). Improvements were seen in the mean Clinical Global Impression of Change scores for both the arbaclofen extended-release 40 mg/day and placebo groups; however, no statistically significant difference was observed between them (least squares mean difference: -0.10; P = 0.43). Most adverse events were of mild-moderate severity. Arbaclofen extended-release 40 mg/day for 12 weeks significantly reduced multiple sclerosis-related spasticity compared with placebo and was safe and well tolerated over the 12-week treatment period. Although arbaclofen extended-release 40 mg/day improved Clinical Global Impression of Change scores, a significant difference from placebo was not observed.