BOTOX® Treatment in Pediatric Lower Limb Spasticity

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of BOTOX® (botulinum toxin Type A) in pediatric patients with lower limb spasticity.

Official Title
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BOTOX® Treatment in Pediatric Lower Limb Spasticity: Double-blind Study

Conditions
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Cerebral Palsy, Pediatrics, Muscle Spasticity

Intervention / Treatment
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* Biological: botulinum toxin Type A
* Drug: Normal Saline (Placebo)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Minimum weight of 10 kg/22 lb Cerebral palsy with dynamic muscle contracture /spasticity of the ankle Exclusion Criteria: Muscular dystrophy, myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or mitochondrial disease Uncontrolled epilepsy Botulinum Toxin therapy of any serotype for any condition within the last 6 months History of surgical intervention of the lower study leg or planned surgery of any limb during the study Previous casting of the study limb for spasticity within 6 months or with a dynamic splint within 3 months, or planned casting or dynamic splinting for spasticity of the study limb or affected upper limb during the study

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BOTOX® 4 U/kg<br>Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT). | Biological: botulinum toxin Type A<br>* Participants received intramuscular injections of botulinum toxin Type A into specified muscles of the lower limb on Day 1.<br>* Other names: BOTOX®;|
| Experimental: BOTOX® 8 U/kg<br>Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 U per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT. | Biological: botulinum toxin Type A<br>* Participants received intramuscular injections of botulinum toxin Type A into specified muscles of the lower limb on Day 1.<br>* Other names: BOTOX®;|
| Placebo Comparator: Normal Saline (Placebo)<br>Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb on Day 1. Participants received weekly PT. | Drug: Normal Saline (Placebo)<br>* Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb on Day 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Ankle Score With Knee Extended at Weeks 4 and 6 | The MAS-B was used to evaluate spasticity based on grading the resistance encountered in the principal muscle group (elbow and wrist) by means of passively moving a limb through its range of motion at a study specified velocity. The resistance encountered to passive stretch was graded using a 6-point scale where: 0=no increase in muscle tone (best) to 4=affected part(s) rigid in flexion or extension (worst). For analysis purposes, the MAS-B was recoded as follows: 0=1, 1=1, 1+=2, 2=3, 3=4, 4=5. The scores at Weeks 4 and 6 were averaged. A Mixed Model Repeated Measures (MMRM) model was used for analysis. A negative change from Baseline indicates improvement. | Baseline (Day 1) to Weeks 4 and 6 | 
| Average Clinical Global Impression (CGI) of Overall Change by Physician at Weeks 4 and 6 | The CGI of overall change (improvement or worsening) was assessed by the physician considering the participant's clinical condition and severity of side effects using a 9-point scale where: -4=very marked worsening to +4=very marked improvement. The scores at Weeks 4 and 6 were averaged. A Mixed Model Repeated Measures (MMRM) model was used for analysis. | Weeks 4 and 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Goal Attainment Score (GAS) as Assessed by Physician Using a 6-Point Scale | Two functional goals, one active and one passive, were selected by the participant and family in consultation with the physician investigator and/or treating physical therapist relative to the lower limb impairment due to spasticity. The physician assessed the achievement of the goals using a 6-point scale: where -3=worse than start to +2=much more than expected: improvements clearly exceed the defined therapeutic goal. An Analysis of Covariance (ANCOVA) model was used for analysis. | Weeks 8 and 12 | 
| Change From Baseline in Severity of Spasticity of the Ankle With Knee Extended and Knee Flexed (R2-R1) Calculated Using the Modified Tardieu Scale (MTS) | The MTS measured the difference between slow and fast range of motion (R2-R1) and respective change from baseline to each posttreatment office visit. The MTS of the ankle was used to determine the passive range of movement at different movement velocities, V1 (as slow as possible) and V3 (as fast as possible) with the relative difference between a slow and fast velocity passive stretch determining the dynamic component of the muscle contracture for the joint. The investigator measured 2 joint angles by goniometer: the R1 angle which is the angle of catch after a fast velocity (V3) stretch and the R2 angle defined as the passive joint range of movement following a slow velocity (V1) stretch. The R2-R1 value indicated the level of the dynamic component of spasticity in the joint. The difference between R2 and R1 range of motion and respective change from baseline to each posttreatment office visit on the MTS was derived. An Analysis of Covariance (ANCOVA) model was used for analysis. | Baseline (Day 1) to Weeks 2, 4, 6, 8 and 12 |