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

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.

Keywords: Botulinum toxin; all movement disorders; all paediatric; cerebral palsy; incobotulinum; spasticity.

Conflict of interest statement

Florian Heinen has received speaker’s honoraria from Allergan plc, Desitin, Ipsen Biopharmaceuticals, Merz Pharmaceuticals, and Novartis and unrestricted educational grants from Allergan and Merz Pharmaceuticals. Petr Kanovský has received speaker’s honoraria from Desitin, Ipsen Biopharmaceuticals, Merz Pharmaceuticals, and Medtronic. A. Sebastian Schroeder has received speaker’s honoraria from and participated in advisory boards for Allergan plc, Ipsen Biopharmaceuticals, and Merz Pharmaceuticals. Henry G. Chambers serves as a consultant for Orthopediatrics Corp and Allergan Corporation. Edward Dabrowski has participated in an advisory board and speaker bureau for Ipsen Biopharmaceuticals. Thorin L. Geister is an employee of Merz Pharmaceuticals GmbH. Angelika Hanschmann is an employee of Merz Pharmaceuticals GmbH. Francisco J. Martinez-Torres is a former employee of Merz North America LLC. Irena Pulte is an employee of Merz Pharmaceuticals GmbH. Marta Banach has served as a consultant and speaker and participated in an advisory board for Merz Pharmaceuticals and has served as a speaker for Allergan, Ipsen, and Kedrion. Deborah Gaebler-Spira has served as a consultant for Teva and Kashiva.

Figures

Figure 1.

Treatment according to (A) clinical patterns and (B) study design. aStudy visits ± 3 days. bAdditional bi-weekly TC to check for eligibility for reinjection. cAdditional control visits every 6 or 8 weeks from 14 weeks up to 36 weeks after each injection. Patients were randomized to one of three dose levels, and U is the maximum dose divided between the muscles at each site. The bilateral clinical pattern refers to treatment of pes equinus in both LLs, and the unilateral clinical pattern refers to treatment of pes equinus on one side and either ipsilateral adducted thigh or ipsilateral flexed knee. BW = body weight; IC = injection cycle; kg = kilogram; LL = lower limb; TC = telephone contact; U = Unit.

Figure 2.

Patient disposition. *Multiple entries possible. **Subjects who completed IC1 and continued to IC2. BW = body weight; IC = injection cycle; kg = kilogram; U = unit.

Figure 3.

The effect of incobotulinumtoxinA on mean change from baseline at week 4 on the AS-PF on the primary body side, FAS, OC. AS score: 5-point scale from 0 (no increase in muscle tone) to 4 (limb rigid in flexion or extension). The change in the AS-PF from baseline to week 4 was the primary efficacy variable. ***p< 0.0001 versus study baseline. AS = Ashworth Scale; AS-PF = Ashworth Scale of the plantar flexors; BW = body weight; FAS = full analysis set; IC = injection cycle; kg = kilogram; OC = observed cases; SE = standard error; U = unit.

Figure 4.

The effect of incobotulinumtoxinA on investigator’s GICS-PF score at week 4; FAS, OC. Investigators were asked to rate their overall impression of change in spasticity of the PFs compared with the condition before the last injection; positive values indicate better results. Investigator’s GICS-PF score at week 4 was the coprimary efficacy variable. ***p< 0.0001. BW = body weight; FAS = full analysis set; GICS-PF = Global Impression of Change of Plantar Flexor Spasticity Scale; IC = injection cycle; kg = kilogram; OC = observed cases; SE = standard error; U = unit.

Figure 5.

The effect of incobotulinumtoxinA on mean change from baseline on week 4 on AS as measured on the (A) knee flexors and (B) thigh adductor muscles, FAS, OC. **p< 0.05 versus study baseline. AS = Ashworth Scale; BW = body weight; FAS = full analysis set; IC = injection cycle; kg = kilogram; OC = observed cases; SE = standard error; U = unit.

Figure 6.

The effect of incobotulinumtoxinA on (A) investigator, (B) parent/caregiver, and (C) child/adolescent GICS scores† at week 4, FAS, OC. †GICS scores were available from 150 of 311 and 135 of 287 children/adolescents (48% and 47.0%) at IC1 and IC2. The proportion of children/adolescents responding was attributed to the respondents’ young age or their cognitive abilities. ***P< 0.0001. BW = body weight; FAS = full analysis set; GICS = Global Impression of Change Scale; IC = injection cycle; kg = kilogram; OC = observed cases; SE = standard error; U = unit.