Efficacy and safety of abobotulinumtoxinA for upper limb spasticity in children with cerebral palsy: a randomized repeat-treatment study.

AIM: To assess the efficacy and safety of repeat abobotulinumtoxinA injections in reducing upper limb spasticity in children with cerebral palsy (CP). METHOD: This was a double-blind, repeat-cycle study (NCT02106351) in children with CP (2-17y). Children were randomized to receive 2U/kg (control), 8U/kg, or 16U/kg abobotulinumtoxinA injections into the target muscle group (wrist or elbow flexors) and additional muscles alongside occupational therapy via a home-exercise therapy program (HETP; minimum five 15min sessions/wk). Children received 8U/kg or 16U/kg plus HETP in cycles 2 to 4. RESULTS: During cycle 1, 210 children (126 males, 84 females; mean age [SD] 9y [4y 5mo], range 2-17y; n=70/group) had at least one upper limb abobotulinumtoxinA injection and 209 complied with the HETP. At week 6 of cycle 1, children in the 8U/kg or 16U/kg groups had significantly lower Modified Ashworth scale scores versus the 2U/kg group (primary outcome: treatment differences of -0.4 [p=0.012] and -0.7 [p<0.001] respectively). All groups improved on Physician Global Assessment and children in all groups achieved their treatment goals at least as expected. Therapeutic benefits were sustained during cycles 2 to 4; muscular weakness was the only treatment-related adverse event reported in at least one child/group (4.3% and 5.7% vs 1.4% respectively). INTERPRETATION: Treatment with 8U/kg or 16U/kg abobotulinumtoxinA significantly reduced upper limb spasticity versus the 2U/kg control dose. Therapeutic benefits of abobotulinumtoxinA plus HETP were sustained with repeat treatment cycles. WHAT THIS PAPER ADDS: AbobotulinumtoxinA injections significantly reduced upper limb spasticity in children with cerebral palsy. Children treated with abobotulinumtoxinA and targeted home exercises showed global improvement and goal attainment. Benefits were sustained over 1 year with repeat cycles of abobotulinumtoxinA and home exercises. AbobotulinumtoxinA injections into the upper limb were well tolerated over 1 year.

Spasticity-related pain in children/adolescents with cerebral palsy. Part 2: IncobotulinumtoxinA efficacy results from a pooled analysis.

PURPOSE: This pooled analysis of data from three Phase 3 studies investigated the effects of incobotulinumtoxinA on spasticity-related pain (SRP) in children/adolescents with uni-/bilateral cerebral palsy (CP). METHODS: Children/adolescents (ambulant and non-ambulant) were evaluated for SRP on increasingly difficult activities/tasks 4 weeks after each of four incobotulinumtoxinA injection cycles (ICs) using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to lower limb [LL] or upper limb [UL] spasticity and respondent type [child/adolescent, interviewer, or parent/caregiver]). IncobotulinumtoxinA doses were personalized, with all doses pooled for analysis. RESULTS: QPS key item responses were available from 331 and 155 children/adolescents with LL- and UL-spasticity, respectively, and 841/444 (LL/UL) of their parents/caregivers. IncobotulinumtoxinA efficacy was evident with the first IC. Efficacy was sustained and became more robust with further subsequent ICs. By Week 4 of the last (i.e. fourth) IC, 33.8-53.3% of children/adolescents reported complete SRP relief from their baseline pain for respective QPS items. Children/adolescents reported reductions in mean LL SRP intensity at levels that surpassed clinically meaningful thresholds. Similarly, parents/caregivers observed complete SRP relief and less frequent SRP with incobotulinumtoxinA. Similar results were found for UL SRP. CONCLUSION: These findings indicate that incobotulinumtoxinA could bring considerable benefit to children/adolescents with spasticity by reducing SRP, even during strenuous activities.

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

PURPOSE: A large prospective database from three Phase 3 studies allowed the study of spasticity-related pain (SRP) in pediatric cerebral palsy (CP). METHODS: Baseline (pretreatment) SRP data occurring during different activities in children/adolescents (aged 2-17 years, ambulant/nonambulant) with uni-/bilateral spastic CP was obtained using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to spasticity level [lower limb (LL) or upper limb (UL)] and type of respondent [child/adolescent, interviewer, or parent/caregiver]). RESULTS: At baseline, 331 children/adolescents with LL- and 155 with UL-spasticity completed at least one key item of their modules; LL/UL QPS modules of parent/caregivers were at least partially completed (key items) by 841/444 parents/caregivers. SRP with at least one activity at baseline was self-reported in 81.9% /69.7% (LLs/ULs) of children/adolescents with spasticity. Parents/caregivers observed LL/UL SRP behaviors in 85.9% /77.7% of their children, with multiple body regions affected. SRP negatively affected the great majority of the children in various ways. Child/adolescent-reported mean SRP intensity and parent/caregiver-observed mean SRP behavior frequencies were higher for LLs than ULs, and the level of SRP increased with more physically demanding activities. CONCLUSION: These data suggest SRP is more common and intense in pediatric CP than generally thought, emphasizing the need for effective, long-term pain management.

Safety Profile and Lack of Immunogenicity of IncobotulinumtoxinA in Pediatric Spasticity and Sialorrhea: A Pooled Analysis.

IncobotulinumtoxinA, a pure botulinumtoxinA formulation, is free of accessory proteins. This analysis provides pooled safety data from phase 3 trials of children/adolescents (2-17 years), investigating incobotulinumtoxinA for the treatment of spasticity associated with cerebral palsy (at doses ≤20 U/kg (max. 500 U) per injection cycle (IC) for ≤6 ICs; three trials) or sialorrhea associated with neurologic disorders (at total doses of 20-75 U per IC for ≤4 ICs; one trial) for ≤96 weeks. Safety endpoints included the incidences of different types of treatment-emergent adverse events (TEAEs) and immunogenicity. IncobotulinumtoxinA dose groups were combined. Of 1159 patients (mean age 7.3 years, 60.4% males) treated with incobotulinumtoxinA, 3.9% experienced treatment-related TEAEs, with the most common being injection site reactions (1.3%) (both indications), muscular weakness (0.7%) (spasticity), and dysphagia (0.2%) (sialorrhea). Two patients (0.2%) experienced a treatment-related treatment-emergent serious adverse event, and 0.3% discontinued the study due to treatment-related TEAEs. No botulinumtoxinA-naïve patients developed neutralizing antibodies (NAbs) after incobotulinumtoxinA. All children/adolescents with known pre-treatment status and testing positive for Nabs at final visit (n = 7) were previously treated with a botulinumtoxinA other than incobotulinumtoxinA. IncobotulinumtoxinA was shown to be safe, with very few treatment-related TEAEs in a large, diverse cohort of children/adolescents with chronic conditions requiring long-term treatment and was without new NAb formation in treatment-naïve patients.

Goal Attainment after Treatment with Abobotulinumtoxina and a Tailored Home Therapy Programme in Children with Upper Limb Spasticity: Descriptive, Exploratory Analysis of a Large Randomized, Controlled Study

OBJECTIVE: This exploratory analysis of a large, randomized, double-blind study (NCT02106351) describes the effect of treatment with abobotulinumtoxinA followed by a tailored home exercises therapy programme in enabling children with upper limb spasticity due to cerebral palsy to achieve their functional goals using goal attainment scaling (GAS). METHODS: Children with cerebral palsy and spasticity in ≥ 1 upper limb received up to 4 injection cycles of abobotulinumtoxinA (2 U/kg (cycle 1 only), 8U/kg and 16U/kg) into the elbow and wrist flexors and other upper limb muscles selected to support individual treatment goals. Children followed a home exercises therapy programme, which included stretches and exercises specifically chosen to facilitate goal achievement and engagement in activities. RESULTS: For cycle 1, most children had active function goals set as their primary goal (69.7% vs 19.2% passive function goals). GAS T- scores and goal responder rates at week 16 indicated that most types of primary goal were achieved at least as expected during cycle 1 (all groups). Primary goal GAS T-scores were generally maintained for the first 3 abobotulinumtoxinA treatment cycles. CONCLUSION: Most children with upper limb spasticity treated with repeat cycles of abobotulinumtoxinA supported by an individualized home exercises therapy programme achieved their functional goals.

Safety and efficacy of repeat long-term incobotulinumtoxinA treatment for lower limb or combined upper/lower limb spasticity in children with cerebral palsy.

PURPOSE: The open-label phase 3 "Treatment with IncobotulinumtoxinA in Movement Open-Label" (TIMO) study investigated longer-term safety and efficacy of incobotulinumtoxin A in children/adolescents with cerebral palsy (CP). METHODS: Patients on standard treatment, with unilateral or bilateral lower limb (LL) or combined upper limb (UL)/LL spasticity received four incobotulinumtoxinA injection cycles (16 or 20 Units/kg bodyweight total [maximum 400 or 500 Units] per cycle depending on ambulatory status/clinical pattern treated), each followed by 12-16 weeks' observation. Treatment for pes equinus was mandatory; flexed knee or adducted thigh were options for unilateral treatment and/or ULs for unilateral/bilateral treatment. The primary endpoint was safety; changes in Ashworth Scale and Gross Motor Function Measure-66 scores, and Global Impression of Change Scale scores at week 4 of each injection cycle were also evaluated. RESULTS: IncobotulinumtoxinA (≤500 Units for ≤98 weeks) was safe, well-tolerated, and effective across all endpoints for multipattern treatment of LL and combined LL/UL spasticity in ambulant/nonambulant children/adolescents with CP. Treatment effects increased with each injection cycle. No new/unexpected safety concerns were identified. CONCLUSION: IncobotulinumtoxinA showed a good safety and tolerability profile, with efficacy over multiple clinical presentations. As an adjunct treatment, it offers an effective, individualized treatment option for pediatric CP-related spasticity.

Therapeutic Effectiveness of AxioBionics Wearable Therapy Pain Management System in Patients with Chronic Lower Back Pain.

Chronic lower back pain is one of the most common medical conditions leading to a significant decrease in quality of life. This study retrospectively analyzed whether the AxioBionics Wearable Therapy Pain Management (WTPM) System, a customized and wearable electrical stimulation device, alleviated chronic lower back pain, and improved muscular function. This study assessed self-reported pain levels using the visual analog scale before and during the use of the AxioBionics WTPM System when performing normal activities such as sitting, standing, and walking (n = 69). Results showed that both at-rest and activity-related pain were significantly reduced during treatment with the AxioBionics WTPM System (% reduction in pain: 64% and 60%, respectively; P < .05). Thus, this study suggests that the AxioBionics WTPM System is efficacious in treating chronic lower back pain even when other therapies have failed to sufficiently decrease reported pain levels.

IncobotulinumtoxinA Efficacy/Safety in Upper-Limb Spasticity in Pediatric Cerebral Palsy: Randomized Controlled Trial.

BACKGROUND: This randomized phase 3 study with double-blind main period (MP) and open-label extension (OLEX; NCT02002884) assessed incobotulinumtoxinA safety and efficacy for pediatric upper-limb spasticity treatment in ambulant/nonambulant (Gross Motor Function Classification System [GMFCS] I-V) patients, with the option of combined upper- and lower-limb treatment. METHODS: Patients were aged two to 17 years with unilateral or bilateral spastic cerebral palsy (CP) and Ashworth Scale (AS) score ≥2 in treatment-selected clinical patterns. In the MP, patients were randomized (2:1:1) to incobotulinumtoxinA 8, 6, or 2 U/kg body weight (maximum 200, 150, 50 U/upper limb), with optional lower-limb injections in one of five topographical distributions (total body dose ≤16 to 20 U/kg, maximum 400 to 500 U, depending on body weight and GMFCS level). In the OLEX, patients received three further treatment cycles, at the highest MP doses (8 U/kg/upper limb group). Outcomes included AS, Global Impression of Change Scale (GICS), and adverse events (AEs). RESULTS: AS scores improved from baseline to week 4 in all MP dose groups (n = 350); patients in the incobotulinumtoxinA 8 U/kg group had significantly greater spasticity improvements versus the 2 U/kg group (least-squares mean [standard error] for upper-limb main clinical target pattern -1.15 [0.06] versus -0.93 [0.08]; P = 0.017). Investigator's, child/adolescent's, and parent/caregiver's GICS scores showed improvements in all groups. Treatment benefits were sustained over further treatment cycles. AE incidence did not increase with dose or repeated treatment across GMFCS levels. CONCLUSIONS: Data provide evidence for sustained efficacy and safety of multipattern incobotulinumtoxinA treatment in children and adolescents with upper-limb spasticity.

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

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.

Muscle Selection and Dosing in a Phase 3, Pivotal Study of AbobotulinumtoxinA Injection in Upper Limb Muscles in Children With Cerebral Palsy.

Background: Guidelines recommend botulinum toxin-A in pediatric upper limb spasticity as part of routine practice. Appropriate dosing is a prerequisite for treatment success and it is important that injectors have an understanding on how to tailor dosing within a safe and effective range. We report upper limb dosing data from a phase 3 study of abobotulinumtoxinA injections in children with cerebral palsy. Methods: This was a double-blind, repeat-treatment study (NCT02106351). In Cycle 1, children were randomized to abobotulinumtoxinA at 2 U/kg control dose or clinically relevant 8 U/kg or 16 U/kg doses. Doses were divided between the primary target muscle group (PTMG, wrist or elbow flexors) and additional muscles tailored to clinical presentation. During Cycles 2-4, children received doses of 8 U/kg or 16 U/kg and investigators could change the PTMG and other muscles to be injected. Injection of muscles in the other upper limb and lower limbs was also permitted in cycles 2-4, with the total body dose not to exceed 30 U/kg or 1,000 U (whichever was lower) in the case of upper and lower limb treatment. Results: 212 children were randomized, of which 210 received ≥1 abobotulinumtoxinA injection. Per protocol, the elbow and wrist flexors were the most commonly injected upper limb muscles. Across all 4 cycles, the brachialis was injected in 89.5% of children (dose range 0.8-6 U/kg), the brachioradialis in 83.8% (0.4-3 U/kg), the flexor carpi ulnaris in 82.4% (0.5-3 U/kg) and the flexor carpi radialis in 79.5% (0.5-4 U/kg). Other frequently injected upper limb muscles were the pronator teres(70.0%, 0.3-3 U/kg). adductor pollicis (54.3%, 0.3-1 U/kg), pronator quadratus (44.8%, 0.1-2 U/kg), flexor digitorum superficialis (39.0%, 0.5-4 U/kg), flexor digitorum profundus (28.6%, 0.5-2 U), flexor pollicis brevis/opponens pollicis (27.6%, 0.3-1 U/kg) and biceps (27.1%, 0.5-6 U/kg). AbobotulinumtoxinA was well-tolerated at these doses; muscular weakness was reported in 4.3% of children in the 8 U/kg group and 5.7% in the 16 U/kg group. Conclusions: These data provide information on the pattern of injected muscles and dose ranges used in this study, which were well-tolerated. Per protocol, most children received injections into the elbow and wrist flexors. However, there was a wide variety of other upper limb muscles injected as physicians tailored injection patterns to clinical need.

Efficacy of Repeat AbobotulinumtoxinA (Dysport®) Injections in Improving Gait in Children with Spastic Cerebral Palsy.

Purpose: This secondary analysis of a randomized, double-blind study plus open-label extension (NCT01249417/NCT01251380) evaluated the efficacy of abobotulinumtoxinA versus placebo in improving gait pattern in children with dynamic equinus due to cerebral palsy (CP) as assessed by the observational gait scale (OGS). Methods: Ambulatory children with CP (N = 241, aged 2-17) and dynamic equinus were randomized to treatment with abobotulinumtoxinA (10 or 15U/kg/leg) or placebo injected into the gastrocsoleus. All children received abobotulinumtoxinA in the open-label phase. Results: In the double-blind phase, abobotulinumtoxinA significantly improved OGS total scores versus placebo at Week 4 (treatment effect vs. placebo: 10U/kg/leg: 1.5 [0.7, 2.3], p = .0003; 15U/kg/leg: 1.1 [0.3, 1.9], p = .01). In the open-label phase, treatment with abobotulinumtoxinA continued to improve the OGS score at the same magnitude as seen in the double-blind study. Conclusion: Repeat treatment with abobotulinumtoxinA improved gait in children with dynamic equinus.

AbobotulinumtoxinA Efficacy and Safety in Children With Equinus Foot Previously Treated With Botulinum Toxin.

BACKGROUND: The effects of botulinum toxin are transient, and repeat injections are required in children with lower-limb spasticity. However, the efficacy of botulinum toxin in patients who have received previous injections has remained largely unexplored. METHODS: We present subgroup analyses of a phase III study conducted in ambulatory children (aged two to 17) with spastic equinus foot. Patients were randomized to single doses of abobotulinumtoxinA 10 U/kg/leg, 15 U/kg/leg, or placebo injected into the gastrocnemius-soleus complex (one or both legs). The first analysis was prespecified to review the effect of abobotulinumtoxinA in children previously treated with botulinum toxin versus those children new to the treatment; a second post hoc analysis evaluated the effect of abobotulinumtoxinA in children who changed botulinum toxin formulation. RESULTS: Of the 241 randomized patients, 113 had previously received botulinum toxin, including 86 who had been treated with another formulation. In both analyses, muscle tone (Modified Ashworth Scale) and the Physicians Global Assessment, at week 4, improved with abobotulinumtoxinA treatment versus placebo, regardless of baseline botulinum toxin status. Placebo responses in patients new to treatment were consistently higher than in the previously treated group. CONCLUSIONS: These results demonstrate similar abobotulinumtoxinA efficacy and safety profiles in children with spasticity who are new to botulinum toxin treatment and those children who were previously treated. The efficacy and safety of abobotulinumtoxinA treatment in these previously treated patients were comparable with the overall trial population, indicating that doses of 10 and 15 U/kg/leg are suitable starting doses for children with spasticity regardless of the previous botulinum toxin preparation used.

Safety and Efficacy of Repeat Open-Label AbobotulinumtoxinA Treatment in Pediatric Cerebral Palsy.

This was a prospective, repeat-treatment, open-label study (NCT01251380) of abobotulinumtoxinA for the management of lower limb spasticity in children who had completed a double-blind study. Children (2-17 years) received injections into the gastrocnemius-soleus complex, and other distal and proximal muscles as required (maximum total dose per injection cycle: 30 U/kg or 1000U). A total of 216 of the 241 double-blind patients entered the extension study and 207 received ≥1 open label injection into the gastrocnemius-soleus; 17-24% of patients also had injections into the hamstrings. The most frequent adverse events were related to common childhood infections and the most frequent treatment-related adverse event was injection site pain (n = 10). There was no evidence of a cumulative effect on adverse events. Sustained significant clinical improvements in muscle tone (Modified Ashworth Scale), spasticity (Tardieu Scale), overall clinical benefit (Physicians Global Assessment), and goal attainment (Goal Attainment Scale) were also observed across treatment cycles.

AbobotulinumtoxinA for Equinus Foot Deformity in Cerebral Palsy: A Randomized Controlled Trial.

BACKGROUND: Although botulinum toxin is a well-established treatment of focal spasticity in cerebral palsy, most trials have been small, and few have simultaneously assessed measures of muscle tone and clinical benefit. METHODS: Global, randomized, controlled study to assess the efficacy and safety of abobotulinumtoxinA versus placebo in cerebral palsy children with dynamic equinus foot deformity. Patients were randomized (1:1:1) to abobotulinumtoxinA 10 U/kg/leg, 15 U/kg/leg, or placebo injections into the gastrocnemius-soleus complex (1 or both legs injected). In the primary hierarchical analysis, demonstration of benefit for each dose required superiority to placebo on the primary (change in Modified Ashworth Scale from baseline to week 4) and first key secondary (Physician's Global Assessment at week 4) end points. RESULTS: Two hundred and forty-one patients were randomized, and 226 completed the study; the intention to treat population included 235 patients (98%). At week 4, Modified Ashworth Scale scores significantly improved with abobotulinumtoxinA; mean (95% confidence interval) treatment differences versus placebo were -0.49 (-0.75 to -0.23; P = .0002) for 15 U/kg/leg and -0.38 (-0.64 to -0.13; P = .003) for 10 U/kg/leg. The Physician's Global Assessment treatment differences versus placebo of 0.77 (0.45 to 1.10) for 15 U/kg/leg and 0.82 (0.50 to 1.14) for 10 U/kg/leg were also significant (both Ps < .0001). The most common treatment-related adverse event was muscular weakness (10 U/Kg/leg = 2; placebo = 1). CONCLUSIONS: AbobotulinumtoxinA improves muscle tone in children with dynamic equinus resulting in an improved overall clinical impression and is well tolerated.

Robotic-assisted treadmill therapy improves walking and standing performance in children and adolescents with cerebral palsy.

OBJECTIVE: Task-specific body-weight-supported treadmill therapy improves walking performance in children with central gait impairment. The aim of the study was to investigate the effect of robotic-assisted treadmill therapy on standing and walking performance in children and adolescents with cerebral palsy and to determine parameters influencing outcome. METHODS: 20 Patients (mean age 11.0 ± 5.1, 10 males and 10 females) with cerebral palsy underwent 12 sessions of robotic-assisted treadmill therapy using the driven gait orthosis Lokomat. Outcome measures were the dimensions D (standing) and E (walking) of the Gross Motor Function Measure (GMFM). RESULTS: Significant improvements in dimension D by 5.9% (± 5.2, p=0.001) and dimension E by 5.3% (± 5.6, p<0.001) of the GMFM were achieved. Improvements in the GMFM D and E were significantly greater in the mildly affected cohort (GMFCS I and II) compared to the more severely affected cohort (GMFCS III and IV). Improvement of the dimension E but not of D correlated positively with the total distance and time walked during the trial (r(s)=0.748, p<0.001). CONCLUSIONS: Children and adolescents with bilateral spastic cerebral palsy showed improvements in the functional tasks of standing and walking after a 3-week trial of robotic-assisted treadmill therapy. The severity of motor impairment affects the amount of the achieved improvement.

Botulinum toxin as a novel treatment for self-mutilation in Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder resulting from a deficiency of the metabolic enzyme hypozanthine-guanine phosphoribosyltransferase (HPRT). This syndrome presents with abnormal metabolic and neurological manifestations including hyperuricemia, mental retardation*, spastic cerebral palsy (CP), dystonia, and self-mutilation. The mechanism behind the severe self-mutilating behavior exhibited by patients with LNS is unknown and remains one of the greatest obstacles in providing care to these patients. This report describes a 10-year-old male child with confirmed LNS who was treated for self-mutilation of his hands, tongue, and lips with repeated botulinum toxin A (BTX-A) injections into the bilateral masseters. Our findings suggest that treatment with BTX-A affects both the central and peripheral nervous systems, resulting in reduced self-abusive behavior in this patient.