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

ABSTRACT: 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.

SUBMITTER: Oleszek J

PROVIDER: S-EPMC8603760 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimTo assess the efficacy and safety of repeat abobotulinumtoxinA injections in reducing upper limb spasticity in children with cerebral palsy (CP).MethodThis 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.ResultsDuring 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).InterpretationTreatment 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 addsAbobotulinumtoxinA 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.

Project description:Background: In children with unilateral cerebral palsy (uCP) virtually nothing is known on the relation between structural brain damage and upper limb (UL) kinematics quantified with three-dimensional movement analysis (3DMA). This explorative study aimed to (1) investigate differences in UL kinematics between children with different lesion timings, i.e., periventricular white matter (PWM) vs. cortical and deep gray matter (CDGM) lesions and (2) to explore the relation between UL kinematics and lesion location and extent within each lesion timing group. Methods: Forty-eight children (age 10.4 ± 2.7 year; 29 boys; 21 right-sided; 33 PWM; 15 CDGM) underwent an UL 3DMA during a reach-to-grasp task. Spatiotemporal parameters [movement duration, (timing of) maximum velocity, trajectory straightness], the Arm Profile Score (APS) and Arm Variable Scores (AVS) were extracted. The APS and AVS refer to the total amount of movement pathology and movement deviations of the wrist, elbow, shoulder, scapula and trunk respectively. Brain lesion location and extent were scored based on FLAIR-images using a semi-quantitative MRI-scale. Results: Children with CDGM lesions showed more aberrant spatiotemporal parameters (p < 0.03) and more movement pathology (APS, p = 0.003) compared to the PWM group, mostly characterized by increased wrist flexion (p = 0.01). In the CDGM group, moderate to high correlations were found between lesion location and extent and duration, timing of maximum velocity and trajectory straightness (r = 0.53-0.90). Lesion location and extent were further moderately correlated with distal UL movement pathology (wrist flexion/extension, elbow pronation/supination, elbow flexion/extension; r = 0.50-0.65) and with the APS (r = 0.51-0.63). In the PWM group, only a few and low correlations were observed, mostly between damage to the PLIC and higher AVS of elbow flexion/extension, shoulder elevation and trunk rotation (r = 0.35-0.42). Regression analysis revealed damage to the temporal lobe with lesion timing as interactor (27%, p = 0.002) and the posterior limb of the internal capsule (PLIC) (7%, p = 0.04) as the strongest predictors, explaining 34% of the variance in APS. Conclusion: UL kinematic deviations are more influenced by lesion location and extent in children with later (CDGM) versus earlier lesions (PWM), except for proximal movement pathology. Damage to the PLIC is a significant predictor for UL movement pathology irrespective of lesion timing.

Project description:Rehabilitation for children with hemiplegic cerebral palsy (HCP) aimed to improve function of the impaired upper limb (UL) uses a wide range of intervention programs. A new rehabilitative approach, called Action-Observation Therapy, based on the recent discovery of mirror neurons, has been used in adult stroke but not in children. The purpose of the present study is to design a randomised controlled trial (RCT) for evaluating the efficacy of Action-Observation Therapy in improving UL activity in children with HCP.The trial is designed according to CONSORT Statement. It is a randomised, evaluator-blinded, match-pair group trial. Children with HCP will be randomised within pairs to either experimental or control group. The experimental group will perform an Action-Observation Therapy, called UP-CAT (Upper Limb-Children Action-Observation Training) in which they will watch video sequences showing goal-directed actions, chosen according to children UL functional level, combined with motor training with their hemiplegic UL. The control group will perform the same tailored actions after watching computer games. A careful revision of psychometric properties of UL outcome measures for children with hemiplegia was performed. Assisting Hand Assessment was chosen as primary measure and, based on its calculation power, a sample size of 12 matched pairs was established. Moreover, Melbourne and ABILHAND-Kids were included as secondary measures. The time line of assessments will be T0 (in the week preceding the onset of the treatment), T1 and T2 (in the week after the end of the treatment and 8 weeks later, respectively). A further assessment will be performed at T3 (24 weeks after T1), to evaluate the retention of effects. In a subgroup of children enrolled in both groups functional Magnetic Resonance Imaging, exploring the mirror system and sensory-motor function, will be performed at T0, T1 and T2.The paper aims to describe the methodology of a RCT for evaluating the efficacy of Action-Observation Therapy in improving UL activity in children with hemiplegia. This study will be the first to test this new type of treatment in childhood. The paper presents the theoretical background, study hypotheses, outcome measures and trial methodology.NCT01016496.

Project description:AimTo explore cortical activation during bimanual tasks and functional correlates in unilateral cerebral palsy (CP).MethodThis cross-sectional study included eight participants with unilateral CP (six females, two males; mean age [SD] 20y 10mo [5y 10mo], 13y 8mo-31y 6mo) in Manual Ability Classification System levels II to III and nine age-matched participants with typical development (seven females, two males; mean age [SD] 17y 8mo [5y 7mo], 9y 4mo-24y 2mo). They performed bimanual symmetric squeezing (BSS) and bimanual asymmetric squeezing (BAS) tasks at 1Hz, and a pouring task with dominant hand (DPour) and a pouring task with non-dominant hand (NDPour) at 0.67Hz, all while a custom array of functional near-infrared spectroscopy (fNIRS) optodes were placed over their sensorimotor area. Mixed-effects were used to contrast groups, tasks, and hemispheres (corrected p-values [q] reported). Analysis of variance and t-tests compared performance measures across groups and tasks.ResultsParticipants with unilateral CP showed greater activation in both hemispheres during BAS (non-lesioned: q<0.001; lesioned: q<0.001), and in the lesioned hemisphere during BSS (q<0.001), DPour (q=0.02), and NDPour (q=0.02) than those with typical development. The lesioned hemisphere in unilateral CP showed more activity than the non-lesioned one (BSS: q=0.01; BAS: q=0.009; NDPour: q=0.04). During BAS, higher cortical activity correlated with more synchronous arm activation (r=0.79; p=0.02); activity lateralized towards the non-lesioned hemisphere correlated with better Pediatric Evaluation of Disability Inventory computer adaptive test scores (r=0.81; p=0.03).InterpretationResults suggest abnormally increased sensorimotor cortical activity in unilateral CP, with implications to be investigated.What this paper addsCortical activity in manual tasks is described with functional near-infrared spectroscopy in typical and atypical cohorts. Activation levels in unilateral cerebral palsy appear to escalate with task difficulty. Increased brain activity may be associated with poorer selective manual control. Specific patterns of brain activity may be related to impaired bimanual function.

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

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