Background: Arbaclofen, the active R-enantiomer of baclofen, a racemic g-aminobutyric acid-B (GABAB) receptor agonist, has been a mainstay of treatment for people with multiple sclerosis (MS)-associated spasticity. Arbaclofen extended-release (ER) tablets provide sustained concentrations of active drug, allowing for twice-daily dosing.
Objectives: To evaluate the efficacy and safety of arbaclofen ER in patients with MS-related spasticity.
Methods: This Phase 3, double-blind, multi-center study randomized adults with MS-related spasticity to receive twice-daily oral arbaclofen ER (40 mg/day or 80 mg/day) or placebo for 12 weeks. The co-primary efficacy endpoints were change from baseline in Total Numeric-Transformed Modified Ashworth Scale in the Most-Affected Limb (TNmAS-MAL) score and Clinical Global Impression of Change (CGIC) score at Week 12. In a hierarchical testing procedure, analyses for 80 mg/day were considered inferential only if statistically significant differences (p?0.05) were seen between arbaclofen ER 40 mg/day and placebo for both co-primary efficacy endpoints. Secondary analyses included TNmAS score of total limbs (TNmAS-TL), Expanded Disability Status Scale (EDSS) score, and Patient Global Impression of Change (PGIC) score.
Results: 536 patients were enrolled in the study. At Week 12, the least squares (LS) mean change from baseline in TNmAS-MAL score was 1.67 (95% confidence interval [CI]: 1.97, 1.36) and 1.28 (95% CI: 1.57, 0.99) in the arbaclofen ER 40 mg/day and placebo groups, respectively (LS mean difference, 0.39; p<0.05). Improvements were seen in mean CGIC scores for both the arbaclofen ER 40 mg/day and placebo groups, but there was no statistical significance observed between them (LS mean difference, 0.10; p=0.43). Significant improvements were observed in all three treatment groups in the mean change from baseline to Week 12 in the TNmAS-TL and PGIC scores. Mean scores on EDSS remained stable during the study. Treatment-emergent adverse events (TEAEs) were of mild-moderate severity and occurred in 77.1% of the arbaclofen ER 40 mg/day group (n = 138), 83.2% of the arbaclofen ER 80 mg/day group (n = 149), and 71.3% of the placebo group (n = 127). Conclusions: Arbaclofen ER 40 mg/day for 12 weeks significantly reduced MS-related spasticity as measured by the TNmAS-MAL compared with placebo. Twice-daily arbaclofen ER (40 mg/day and 80 mg/day) also appeared to have an acceptable safety profile.