Efficacy and safety of incobotulinumtoxina for upper- or combined upper- and lower-limb spasticity in children and adolescents with cerebral palsy: Results of the phase 3 XARA study

Objective: To assess the efficacy and safety of incobotulinumtoxinA for upper- and combined upper- and lower-limb spasticity in ambulant and non-ambulant children and adolescents with cerebral palsy (CP). Background: IncobotulinumtoxinA is a purified botulinum toxin type A formulation, free from complexing proteins. Design/Methods: XARA (NCT02002884) was a randomized, Phase 3 study with a double-blind main period (MP) and open-label extension (OLEX) period. Patients aged 2-17 years with unior bilateral CP and Ashworth Scale (AS) score ≥2 in main clinical target patterns, flexed elbow and/or wrist, were enrolled. In MP, patients were randomized (2:1:1) to three incobotulinumtoxinA dose groups (8, 6, 2 U/kg body weight [BW]; maximum 200, 150, 50 U/upper limb) with additional lower limb injections (total body dose ≤16-20 U/kg BW [≤400- 500 U], depending on Gross Motor Function Classification System level [GMFCS]). Patients received three further injection cycles (ICs) in OLEX, with doses per the 8 U/kg BW group. Outcomes included AS, Global Impression of Change Scale (GICS), and adverse events (AEs). Results: 350 patients (62.9% male, mean [SD] age 7.3 [4.4] years, BW 25.0 [15.0] kg, 30.9% GMFCS IV-V) were treated; 281 (80.3%) completed the study, receiving four incobotulinumtoxinA ICs. In MP, AS scores for upper limb main clinical pattern improved significantly from baseline to Week 4 (p<0.0001), with significantly greater improvement in the 8 U/kg versus the 2 U/kg dose group (p=0.017). Improvements were observed in all treated upper- and lower-limb clinical patterns and across all OLEX ICs. GICS scores confirmed global improvements in upper- and lower-limb spasticity but did not differ between dose groups. There was no increased incidence of AEs with increasing dose or repeated treatment. Conclusions: This large pediatric study confirmed the efficacy and safety of incobotulinumtoxinA for muscle tone reduction in multi-level, multi-pattern treatment of spasticity in patients with CP (GMFCS I-V).