IncobotulinumtoxinA for the treatment of lower-limb spasticity in children and adolescents with cerebral palsy: A phase 3 study1

Abstract

PURPOSE: Investigate the efficacy and safety of multipattern incobotulinumtoxinA injections in children/adolescents with lower-limb cerebral palsy (CP)-related spasticity. METHODS: Phase 3 double-blind study in children/adolescents (Gross Motor Function Classification System – Expanded and Revised I–V) with unilateral or bilateral spastic CP and Ashworth Scale (AS) plantar flexor (PF) scores ⩾ 2 randomized (1:1:2) to incobotulinumtoxinA (4, 12, 16 U/kg, maximum 100, 300, 400 U, respectively) for two 12- to 36-week injection cycles. Two clinical patterns were treated. Pes equinus (bilateral or unilateral) was mandatory; if unilateral, treatment included flexed knee or adducted thigh. Endpoints: Primary: AS-PF change from baseline to 4 weeks; Coprimary: investigator-rated Global Impression of Change Scale (GICS)-PF at 4 weeks; Secondary: investigator’s, patient’s, and parent’s/caregiver’s GICS, Gross Motor Function Measure-66 (GMFM-66). RESULTS: Among 311 patients, AS-PF and AS scores in all treated clinical patterns improved from baseline to 4-weeks post-injection and cumulatively across injection cycles. GICS-PF and GICS scores confirmed global spasticity improvements. GMFM-66 scores indicated better motor function. No significant differences between doses were evident. Treatment was well-tolerated, with no unexpected treatment-related adverse events or neutralising antibody development. CONCLUSION: Children/adolescents with lower-limb spasticity experienced multipattern benefits from incobotulinumtoxinA, which was safe and well-tolerated in doses up to 16 U/kg, maximum 400 U.

Spasticity-related pain in children/adolescents with cerebral palsy. Part 1: Prevalence and clinical characteristics from a pooled analysis

“…Full details of all three incobotulinumtoxinA studies included in this analysis have already been described [ 31–33 ]. The following provides a brief overview only.…”

“…The aims of TIM, TIMO, and XARA were to investigate the efficacy and safety of incobotulinumtoxinA in children/adolescents with spasticity due to CP. The TIM study was a prospective, multicenter, randomized, double-blind, parallel-group study of children/adolescents with LL spasticity—all of whom had pes equinus—conducted across 45 sites in 14 countries (two injection cycles; N = 311) [ 31 ]. The TIMO study was an open-label, non-controlled, multicenter, long-term study in LL or combined LL and UL spasticity conducted across 30 sites in 12 countries (four injection cycles) [ 32 ].…”

“…To ensure a proper level of spasticity for incobotulinumtoxinA treatment, an Ashworth Scale (AS) score≥2 in prespecified clinical patterns was required. The three studies included patients with a range of LL and/or UL presentations [ 31–33 ], as would be expected in clinical practice. Within 14 weeks prior to the screening visit and/or within the screening period, no BoNT-A treatment was allowed for any body region.…”

“…IncobotulinumtoxinA is a highly purified formulation of BoNT-A (150 kD) that does not contain BoNT complexing proteins [ 30 ]. The study program included TIM (Treatment with IncobotulinumtoxinA in Movement, NCT01893411) [ 31 ], TIMO (Treatment with IncobotulinumtoxinA in Movement Open-label, NCT01905683) [ 32 ], and XARA (incobotulinumtoXinA in aRm treatment in cerebral pAlsy, NCT02002884) [ 33 ]. All three studies enrolled children/adolescents with CP and LL spasticity; in TIMO and XARA, patients could also present with UL spasticity.…”

“…All three studies enrolled children/adolescents with CP and LL spasticity; in TIMO and XARA, patients could also present with UL spasticity. Results from these studies showed that incobotulinumtoxinA is effective and safe for reducing pediatric LL and UL spasticity over multiple injection cycles spanning a total of 24 to 98 weeks [ 31–36 ].…”