Dose response with onabotulinumtoxinA for post-stroke spasticity: A pooled data analysis

Abstract

Clinical trials demonstrate that onabotulinumtoxinA reduces upper limb post-stroke spasticity, with therapeutic response influenced by injected dose. Individual studies provide limited insight regarding muscle group-specific dose-response relationships. Our objective was to characterize dose-response relationships between onabotulinumtoxinA and muscle tone in specific upper limb muscles. Individual patient data from seven multicenter, randomized, double-blind, placebo-controlled trials were pooled. Of 544 post-stroke patients enrolled, 362 received onabotulinumtoxinA and 182 received placebo, injected into the flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP), and/or biceps brachii (BB). Ashworth Scale score change at week 6 (AshworthCBL) was the primary outcome measure for muscle tone. For a broader analysis of response, AshworthCBL/onabotulinumtoxinA dosage relationships were characterized using three techniques: (1) AshworthCBL plotted as a function of onabotulinumtoxinA dose in Units (U) [dose-response curve]; (2) mean AshworthCBL per onabotulinumtoxinA dose depicting the responses seen with specific dose injection clusters/groups for each specific muscle group; and (3) onabotulinumtoxinA dose estimated to produce a mean 1-point decrease in AshworthCBL as an indicator of clinically meaningful benefit of treatment. Increasing onabotulinumtoxinA doses produced greater AshworthCBLs (muscle tone improvements). The maximal week 6 response (E(max)) model indicated a saturating dose-response relationship, with mean E(max) AshworthCBL values of -1.48, -1.48, -0.63, -0.77, and -0.61 in the FCR, FCU, FDS, FDP, and BB, respectively. OnabotulinumtoxinA doses estimated to produce a mean 1-point decrease in AshworthCBL were: 22.5U, 18.4U, 66.3U, 42.5U in the FCR, FCU, FDS, and FDP, respectively, and not determinable in the BB. These analyses demonstrate a saturating effect of greater muscle tone improvements with increasing onabotulinumtoxinA doses in post-stroke spasticity patients. These findings suggest potentially effective onabotulinumtoxinA doses in selected muscle groups in this study population.