Objectives: Assess the efficacy and safety of upper-limb abobotulinumtoxinA injections for spasticity in children with cerebral palsy (CP). Cycle 1 compared abobotulinumtoxinA at doses of 8U/kg and 16U/kg versus a low-dose (2U/kg) control group.
Design: This was a double-blind, repeat treatment (≤4 cycles over 1 year) study (NCT02106351). Children (2-17y) with CP and spasticity in ≥1 upper-limb were randomized (1:1:1) to Cycle 1 injections of abobotulinumtoxinA 8U/kg, 16U/kg or 2U/kg into the primary target muscle group (PTMG; elbow or wrist flexors).The PTMG could change in cycles 2-4 (injection intervals ≥16 weeks), when children received 8U/kg or 16U/kg. All children participated in an individualized home therapy program.
Results: 212 children were randomized and 181 completed the study. Changes in the Modified Ashworth Scale (MAS) score of the PTMG from Baseline to Week 6 of Cycle 1 (primary endpoint) were significantly different for the 8U/kg and 16U/kg abobotulinumtoxinA groups versus 2U/kg control (mean reductions from baseline of -2.0 and -2.3 vs. -1.6, respectively), and statistical difference was maintained at Week 16. All three groups showed a clinically relevant effect on the Physicians Global Assessment (PGA) of treatment response at Week 6 of Cycle 1 (mean improvement of 2.0 grades with 8U/kg and 16U/kg vs. 1.8 grade in the control group), with no significant differences between groups. Benefits were sustained over the 1 year study with repeat abobotulinumtoxinA injections of 8U/kg or 16U/kg. Mean injection intervals (2U/kg, 8U/kg, 16U/kg) were: 22.4, 23.9 and 25.6 weeks, respectively. Adverse events were mostly mild–moderate and reflective of common childhood illnesses.
Conclusions: AbobotulinumtoxinA administered at doses of 8U/kg or 16U/kg in the affected upper-limb significantly reduced spasticity compared to the 2U/kg control dose and was well-tolerated. Treatment was associated with global improvement and therapeutic benefits were sustained with repeat injections of 8U/kg or 16U/kg over one year.
Background: Botulinum toxin is an established therapy for upper limb spasticity in children with cerebral palsy (CP), however evidence from controlled, repeat-cycle studies is lacking. We assessed the efficacy and safety of repeat abobotulinumtoxinA injections in children with CP and upper limb spasticity.
Design: This randomized, controlled, repeat cycle (≤4 cycles) study (NCT02106351) enrolled children aged 2-17 years with CP and upper limb spasticity from 32 specialist clinics in Europe, America and the Middle East. We included a broad range of disease severities, from Gross Motor Function Classification System (GMFCS) Level I to IV.Participants were randomly allocated in a 1:1:1 ratio to receive Cycle 1 injections of abobotulinumtoxinA 2U/kg, 8U/kg or 16U/kg into the primary target muscle group (PTMG; wrist or elbow flexors) and additional muscles according to clinical presentation. Patients and investigators were blinded to treatment allocation. At the start of each treatment cycle, the treating team discussed and agreed upon 1–3 treatment goals with the families and children and selected the study limb and PTMG accordingly. The PTMG could change in repeat cycles 2–4 when children received 8U/kg or 16U/kg. All children participated in a personalized home exercises therapy program (HETP) to provide a standardized background of good practice against which to test the efficacy of abobotulinumtoxinA. The primary endpoint, change in Modified Ashworth Scale (MAS) in PTMG from baseline to Week 6 of Cycle 1, was analyzed usingan analysis of covariance (ANCOVA) of the ranked changes. Secondary efficacy measures were the Physicians Global Assessment (PGA) of treatment response (analysis of variance [ANOVA] of ranked score) and Goal Attainment Scaling (GAS) (ANOVA) assessed at Week 6 of Cycle 1.
Results: 212 children were randomized in the study, of which 210 children entered Cycle 1 (n=70 in each group) and received ≥1 abobotulinumtoxinA injection. Of the 210 treated children, all but one participated in the HETP, with 50.9% (n=107) performing the exercises daily and 32.4% (n=68) performing the exercises 5 or 6 times per week (between Baseline and Week 6). Adjusted mean change in PTMG MAS score from baseline to Week 6 of Cycle 1 was -1.6 in the 2U/kg group, -2.0 in the 8U/kg group (difference -0.4, p=0.0118 vs control), and -2.3 in the 16U/kg group (difference -0.7, p< 0.0001 vs control). MAS scores consistently reduced by about two grades from Baseline to Week 6 of each subsequent treatment cycle, with similar results for children treated with the two study doses (8U/kg and 16U/kg). All three treatment groups showed a clinically relevant effect on PGA scores at Week 6 of Cycle 1. Children treated with abobotulinumtoxinA 8U/kg and 16U/kg groups showed a mean improvement of 2.0 grades while children in the control 2U/kg group showed a mean improvement of 1.8 grades; there was no statistical significance between the groups. Most children across the three treatment arms achieved their GAS primary goal (70.6–75.8%) at Week 6 of Cycle 1. GAS responder rates were higher at Week 16 (81.2–86.4%), indicating a time lag from peak abobotulinumtoxinA effect on MAS to goal attainment.Responder rates for PGA and GAS remained consistently high over repeat cycles of treatment with abobotulinumtoxinA 8U/kg and 16U/kg.The mean time from injection in Cycle 1 to retreatment in Cycle 2 was longer in the abobotulinumtoxinA 8U/kg and 16U/kg groups compared with the 2U/kg group and increased with dose (23.9 ± 10.5 and 25.6 ± 10.3 vs. 22.4 ± 8.2 weeks, respectively). For Cycle 1, most children who received a second injection were retreated between 16–28 weeks, however some patients did not require reinjection until 34 weeks or later (18.7% in the 2U/kg group, 24.5% in the 8U/Kg group and 24.3% in the 16U/kg group). The mean time to retreatment in subsequent treatment cycles was 19.4 weeks following the second injection and 17.4 weeks following the third injection (all doses combined). The most frequently reported TEAEs ( >5% of subjects) in any treatment group during Cycle 1 were related to common childhood infections. Serious TEAEs were reported for 2.9% of children in the 8U/kg and 16U/kg groups versus 4.3% in the 2U/kg group; none were considered study related. Muscular weakness was the only treatment-related TEAE reported in ≥1 child in any group (4.3% and 7.1% vs. 1.4% of children in the 8U/kg and 16U/kg vs. 2U/kg groups) and was mainly mild-moderate and localised.
Conclusions:In this phase 3 study, both study doses (8U/kg and 16U/kg) of abobotulinumtoxinA met the primary endpoint of superiority compared with the control 2U/kg dose in the reduction from baseline in muscle tone as assessed by the MAS during Cycle 1. When combined with a specific home exercises therapy program (on top of ongoing therapy provision), all three treatment arms were associated with global improvement and excellent goal attainment in Cycle 1 until Week 16. However, statistical superiority of the study doses versus the control dose was not shown for the secondary endpoints. Therapeutic benefits of treatment were generally sustained over the study period of up to 1 year and 9 months, with repeat administrations of abobotulinumtoxinA at doses of 8U/kg or 16U/kg in the upper limb muscles and these doses (up to a total body dose of 30U/kg or a maximum of 1000U, when both upper and lower limbs were treated) were well tolerated in this population of children with upper limb spasticity.
Funding: Ipsen Pharma
Stefan Wietek– Director Medical Affairs, Neurology, Ipsen Bioscience
Mauricio Delgado– Professor, University of Texas Southwestern Medical Center and Texas Scottish Rite Hospital for Children
Ann Tilton– Professor of Clinical Neurology Chief, Section of Child Neurology, LSUHSC and Children's Hospital New Orleans
Jorge Carranza– Consultant, Hospital San José Celaya
Nigar Dursun– Director of Pediatric Neurology and Neurorehabilitation, Kocaeli University Faculty of Medicine Department of Physical Medicine and Rehabilitation
Marcin Bonikowski– Director, Mazovian Neuropsychiatry Center
Resa Aydin– Professor, Istanbul Faculty of Medicine, Department of Physical Medicine and Rehabilitation
Iwona Maciag-Tymecka– Consultant, Rehabilitation Center KROK PO KROKU
Joyce Oleszek– Associate Professor, Children's Hospital Colorado
Edward Dabrowski– Director, Beaumont Health, Oakland University School of Medicine
Anne-Sophie Grandoulier– Statistician, Ipsen Pharma
Philippe Picaut– VP R&D, Ipsen Pharma