Efficacy and safety of abobotulinumtoxinA in spastic lower limb: Randomized trial and extension

Abstract

Objective: To demonstrate single abobotulinumtoxinA injection efficacy in lower limb vs placebo for adults with chronic hemiparesis and assess long-term safety and efficacy of repeated injections.

Methods: In a multicenter, double-blind, randomized, placebo-controlled, single-cycle study followed by a 1-year open-label, multiple-cycle extension, adults ≥6 months after stroke/brain injury received one lower limb injection (abobotulinumtoxinA 1,000 U, abobotulinumtoxinA 1,500 U, placebo) followed by ≤4 open-label cycles (1,000, 1,500 U) at ≥12-week intervals. Efficacy measures included Modified Ashworth Scale (MAS) in gastrocnemius-soleus complex (GSC; double-blind primary endpoint), physician global assessment (PGA), and comfortable barefoot walking speed. Safety was the open-label primary endpoint.

Results: After a single injection, mean (95% confidence interval) MAS GSC changes from baseline at week 4 (double-blind, n = 381) were as follows: -0.5 (-0.7 to -0.4) (placebo, n = 128), -0.6 (-0.8 to -0.5) (abobotulinumtoxinA 1,000 U, n = 125; p = 0.28 vs placebo), and -0.8 (-0.9 to -0.7) (abobotulinumtoxinA 1,500 U, n = 128; p = 0.009 vs placebo). Mean week 4 PGA scores were as follows: 0.7 (0.5, 0.9) (placebo), 0.9 (0.7, 1.1) (1,000 U; p = 0.067 vs placebo), and 0.9 (0.7, 1.1) (1,500 U; p = 0.067); walking speed was not significantly improved vs placebo. At cycle 4, week 4 (open-label), mean MAS GSC change reached -1.0. Incremental improvements in PGA and walking speed occurred across open-label cycles; by cycle 4, week 4, mean PGA was 1.9, and walking speed increased +25.3% (17.5, 33.2), with 16% of participants walking >0.8 m/s (associated with community mobility; 0% at baseline). Tolerability was good and consistent with the known abobotulinumtoxinA safety profile.

Conclusions: In chronic hemiparesis, single abobotulinumtoxinA (Dysport Ipsen) administration reduced muscle tone. Repeated administration over a year was well-tolerated and improved walking speed and likelihood of achieving community ambulation.

Clinicaltrialgov identifiers: NCT01249404, NCT01251367.

Classification of evidence: The double-blind phase of this study provides Class I evidence that for adults with chronic spastic hemiparesis, a single abobotulinumtoxinA injection reduces lower extremity muscle tone.

Figure 1. Participant disposition

^aOf the 12 patients in the observational phase, 5 required retreatment and entered cycle 1 and 7 did not require retreatment. Of these 7 patients, 3 withdrew early and 4 completed the study without retreatment. ^bIncluding 2 participants who entered an observational phase and received no further abobotulinumtoxinA (ABO) injections during the study. ^cIn cycles 3 and 4, concomitant treatment of the affected upper limb muscles was allowed.

Figure 2. Main efficacy results (abobotulinumtoxinA [ABO] doses combined)

(A) Gastrocnemius–soleus complex (GSC) Modified Ashworth scale (MAS) and (B) physician global assessment (PGA) mean scores at baseline or week 4 and across treatment cycles and (C) mean change in comfortable barefoot walking speed from baseline and week 4 and week 12 of each cycle. Baseline refers to baseline of double-blind study, prior to first injection. Error bars in A and B show SD. ^aPercentage improvement from baseline. ^bA post hoc analysis compared change from baseline in 10-m walking speed at week 4 vs week 12 across cycles using a model for repeated measures; greater improvement was observed at week 12 compared with week 4 across cycles. DB = double-blind study; LS = least-squared; PBO = placebo.