Dysport® Pediatric Lower Limb Spasticity Follow-on Study

Study Overview
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Brief Summary
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The purpose of this research study was to determine the long term safety and efficacy of repeated treatments with Dysport® used in the treatment of lower limb spasticity in children with dynamic equinus foot deformity due to cerebral palsy.

Official Title
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A Phase III, Prospective, Multicentre, Open Label, Extension Study Assessing the Long Term Safety and Efficacy of Repeated Treatment With DYSPORT® Used in the Treatment of Lower Limb Spasticity in Children With Dynamic Equinus Foot Deformity Due to Cerebral Palsy

Conditions
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Cerebral Palsy, Muscle Spasticity, Children

Intervention / Treatment
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* Biological: Botulinum toxin type A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects were eligible for participation in the study if they met the following criteria: Completion of the double blind study (Study 141) up to the Week 12, Week 16, Week 22 or Week 28 follow up visit. Without any major protocol deviations and/or any ongoing adverse events (AEs), either of which, in the opinion of the Investigator would pose an unacceptable risk to the subject were he/she to continue receiving treatment in this open label extension study. Written informed consent obtained from the child's parent(s)/guardian(s) for this study, and assent from the child when and where applicable. Exclusion Criteria: Subjects were excluded from entering the study for the following reasons: Major limitation in the passive range of motion at the ankle, as defined by maximum ankle dorsiflexion measured by the angle of arrest (XV1) at slow speed <80° (TS angle) in the most affected leg to be injected. Unwillingness or inability to comply with the protocol. Current need for surgery for spasticity of the gastrocnemius-soleus complex (GSC) and/or hamstring muscles (and/or tendons) in the most affected leg to be injected. Treatment with any drug that interferes either directly or indirectly with neuromuscular function (e.g. aminoglycoside antibiotics) or neuroblocking agents used during surgery (e.g. curare) within the last 30 days prior to study medication or a planned treatment with such drugs. Be pregnant and/or lactating. Female subjects, not willing to use contraceptive measures throughout the course of the study if post pubertal and sexually active. An infection at the injection site(s). Planned treatment with any new investigational drug or device during the study period.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dysport<br>Dysport was injected into either one or both lower limbs in up to 4 cycles of treatment, a minimum of 12 weeks apart and up to a maximum of 40 weeks apart. Doses varied from 5 Units (U)/Kg to 20 U/kg for one leg, or from 10 U/Kg to 30 U/kg for two legs, with a maximum dose of no more than 30 U/Kg overall, or 1000 U, whichever was reached first. | Biological: Botulinum toxin type A<br>* Intramuscular (IM) injection on day 1 of each treatment cycle.<br>* Other names: AbobotulinumtoxinA (Dysport®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Reported in the Double Blind (DB) + Open Label (OL) Period. | Adverse events (AEs) were monitored from the time of informed consent to the end of the study. All AEs were elicited by direct, non-leading questioning or by spontaneous reports. | From baseline (Day 1) until end of study (Week 40) of Cycle 1 and up to Week 28 of Cycles 2 to 4. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline (in the DB Study) in the MAS Score in the GSC Assessed at the Ankle Joint of the (Most) Affected Lower Limb | Baseline for the 'change from DB baseline' was defined as the baseline of Study 141 for all treatment cycles. The Modified Ashworth Scale (MAS) is a 6-point scale which measures the intensity of muscle tone by measuring the resistance of the muscle to passive lengthening or stretching. The investigator graded muscle tone in the GSC from 0 (no increase in tone) to 4 (affected parts rigid in flexion or extension). | DB baseline; Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4 | 
| Mean Change From Baseline (Prior to the First Injection Cycle in the Hamstrings) in the MAS Score in the Knee Flexors Assessed at the Knee Joint of the (Most) Affected Lower Limb | Baseline was defined as the value obtained prior to the first injection in the hamstrings. The MAS is a 6-point scale which measures the intensity of muscle tone by measuring the resistance of the muscle to passive lengthening or stretching. The investigator graded muscle tone in the GSC from 0 (no increase in tone) to 4 (affected parts rigid in flexion or extension). | Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Baseline and Week 4 of Treatment Cycle 4. | 
| Mean Change From Baseline (Prior to the First Injection Cycle in Upper Limb Muscle Groups) in the Mean MAS Score for All Injected Upper Limb Muscle Groups From Treatment Cycle 2 Onwards | Baseline was defined as the value obtained prior to the first injection in the upper limb(s). The MAS is a 6-point scale which measures the intensity of muscle tone by measuring the resistance of the muscle to passive lengthening or stretching. The investigator graded muscle tone in the GSC from 0 (no increase in tone) to 4 (affected parts rigid in flexion or extension). No subjects were treated in the upper limb in Treatment Cycle 4. | Baseline and Weeks 4 and 12 of Treatment Cycles 2 and 3. | 
| Mean Physician's Global Assessment (PGA) Score | Global assessment of treatment response based on changes since the first injection in the DB study. PGA Scale of the Treatment Response: Global assessment of treatment response was assessed by asking the Investigator the following question: how would you rate the response to treatment in the subject's lower limb(s) since the first injection in the DB study? Answers were made on a 9 point rating scale (-4: markedly worse, -3: much worse, -2: worse, -1: slightly worse, 0: no change, +1: slightly improved, +2: improved, +3: much improved, +4: markedly improved). | Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4. | 
| Mean Goal Attainment Scale (GAS) Score | Individual goals were defined prior to treatment in each treatment period. The GAS is a functional scale used to measure progress towards individual therapy goals. Individual goals were defined for each subject by the physician, and the child's parents (caregiver) where applicable, prior to treatment. After treatment in each treatment cycle, the GAS for each goal was rated using a defined scale (-2: Much less than expected outcome, -1: Somewhat less than expected outcome, 0: Expected outcome, 1: Somewhat more than expected outcome, and 2: Much more than expected outcome). | Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4 | 
| Mean Change From DB Baseline in Angle of Arrest (XV1) Derived From the Tardieu Scale (TS), in the GSC Assessed at the Ankle Joint of the (Most) Affected Lower Limb | The TS was used to measure spasticity in the GSC at the ankle joint of the (most) affected lower limb. The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity). The mean change from DB baseline in XV1 at slow speed was derived. | DB baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4 | 
| Mean Change From DB Baseline in Angle of Catch (XV3) Derived From the TS, in the GSC Assessed at the Ankle Joint of the (Most) Affected Lower Limb | The TS was used to measure spasticity in the GSC at the ankle joint of the (most) affected lower limb. The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity). The mean change from DB baseline in XV3 at fast speed was derived. | DB baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4 | 
| Mean Change From DB Baseline in Spasticity Angle (X) Derived From the TS, in the GSC Assessed at the Ankle Joint of the (Most) Affected Lower Limb | The TS was used to measure spasticity in the GSC at the ankle joint of the (most) affected lower limb. The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity). X (threshold) was derived as XV1 at slow speed minus XV3 at fast speed and the mean change from DB baseline was calculated. | DB Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4 | 
| Mean Change From DB Baseline in Spasticity Grade (Y) Derived From the TS, in the GSC Assessed at the Ankle Joint of the (Most) Affected Lower Limb | The mean change from baseline (in the DB study) in Y was derived from the TS. Y was graded according to the following scale: Grade 0 - no resistance throughout passive movement (best outcome); Grade 1 - slight resistance throughout passive movement; Grade 2 - clear catch at precise angle, interrupting passive movement, followed by release; Grade 3 - fatigable clonus (less than 10 sec when maintaining pressure) occurring at a precise angle, followed by release; Grade 4 - unfatigable clonus (more than 10 seconds when maintaining pressure) occurring at a precise angle; Grade 5 - joint immovable (worst outcome). Catch without release was graded 0 if XV1=XV3, 'unratable' spasticity otherwise; catch with 'minimal' release was graded 2 if XV3 was consistent and consistently less than XV1. Angle 0 = position of minimal stretch of the tested muscle. For Grades 0 and 1, spasticity angle X = 0 by definition. | DB Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4 | 
| Mean Change From Baseline (Prior to the First Injection Cycle in the Hamstrings) in XV1 Derived From the TS, in the Knee Flexors Assessed at the Knee Joint of the (Most) Affected Lower Limb | The TS was used to measure spasticity in the knee flexors at the knee joint of the (most) affected lower limb. The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity). The mean change from baseline (prior to the first injection cycle in the hamstrings) in XV1 at slow speed was derived. | Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Baseline and Week 4 of Treatment Cycle 4 | 
| Mean Change From Baseline (Prior to the First Injection Cycle in the Hamstrings) in XV3 Derived From the TS, in the Knee Flexors Assessed at the Knee Joint of the (Most) Affected Lower Limb | The TS was used to measure spasticity in the knee flexors at the knee joint of the (most) affected lower limb. The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity). The mean change from baseline (prior to the first injection cycle in the hamstrings) in XV3 at fast speed was derived. | Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Baseline and Week 4 of Treatment Cycle 4 | 
| Mean Change From Baseline (Prior to the First Injection Cycle in the Hamstrings) in X Derived From the TS, in the Knee Flexors Assessed at the Knee Joint of the (Most) Affected Lower Limb | The TS was used to measure spasticity in the knee flexors at the knee joint of the (most) affected lower limb. The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity). X (threshold) was derived as XV1 at slow speed minus XV3 at fast speed and the mean change from baseline (prior to the first injection cycle in the hamstrings) was calculated. | Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Baseline and Week 4 of Treatment Cycle 4 | 
| Mean Change From Baseline (Prior to the First Injection Cycle in the Hamstrings) in Y Derived From the TS, in the Knee Flexors Assessed at the Knee Joint of the (Most) Affected Lower Limb | The mean change from baseline (prior to the first injection cycle in the hamstrings) in Y was derived from the TS. Y was graded according to the following scale: Grade 0 - no resistance throughout passive movement (best outcome); Grade 1 - slight resistance throughout passive movement; Grade 2 - clear catch at precise angle, interrupting passive movement, followed by release; Grade 3 - fatigable clonus (less than 10 sec when maintaining pressure) occurring at a precise angle, followed by release; Grade 4 - unfatigable clonus (more than 10 seconds when maintaining pressure) occurring at a precise angle; Grade 5 - joint immovable (worst outcome). Catch without release was graded 0 if XV1=XV3, 'unratable' spasticity otherwise; catch with 'minimal' release was graded 2 if XV3 was consistent and consistently less than XV1. Angle 0 = position of minimal stretch of the tested muscle. For Grades 0 and 1, spasticity angle X = 0 by definition. | Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Baseline and Week 4 of Treatment Cycle 4 | 
| Mean Change From DB Baseline in the Observational Gait Scale (OGS) Total Score of the (Most) Affected Leg | The OGS is a measurement tool used to objectively quantify positive and negative features (impairments) of the upper motor neurone syndrome. The OGS is useful when children are too young or insufficiently cooperative for instrumented gait analysis. It is based on the Physicians Rating Scale but has some modifications to improve its sensitivity to detect changes following administration of Botulinum Toxin Type A (BTX-A). The OGS total score was calculated as the sum of the individual question scores for Questions 1 to 7, with the highest possible score being 20. The parameters collected were: knee position in midstance, initial foot contact, foot contact at midstance, timing of heel raise, hindfoot at midstance, base of support and gait assistive devices. Higher scores indicate better gait. The mean change from baseline (in the DB study) in the OGS total score of the (most) affected leg was derived. | DB Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4 | 
| Mean Change From DB Baseline in the PedsQL Score (CP Module Scores) at Each Study Visit Except Week 4 | The PedsQL has a disease specific CP module that is relevant to the study population and complements the core modules. The 35-item questionnaire encompassed 7 scales including (1) daily activities (2) school activities (3) movement and balance (4) pain and hurt (5) fatigue (6) eating activities and (7) speech and communication. A 5-point scale was utilised for parent proxy-report: 0 = never a problem; 1 = almost never a problem; 2 = sometimes a problem; 3 = often a problem; 4 = almost always a problem. Each CP score was calculated as follows: (1) Individual item scores were reversed and transformed from a 0-4 scale to a 0-100 scale by assigning 0=100, 1=75, 2=50, 3=25 and 4=0; (2) Each scale score was calculated as the sum of the transformed individual item scores, divided by the number of non-missing items. Higher scores indicated better quality of life (fewer symptoms or problems). A scale score was only calculated if at least 50% of the associated items were non-missing. | Baseline and Week 12 | 
| Mean Change From DB Baseline in the PedsQL Score (Generic Core Scores) at Each Study Visit Except Week 4 | The PedsQL is a validated quality of life questionnaire, designed for children from 2 to 18 years of age. The Generic Core Scale covers four multidimensional scales including physical, emotional, social and school aspects, with three summary scales of total scale score, physical health summary score and psychosocial health summary score. Each generic core scale was calculated as follows: (1) Individual item scores were reversed and transformed from a 0-4 scale to a 0-100 scale by assigning 0=100, 1=75, 2=50, 3=25 and 4=0; (2) Each scale score was calculated as the sum of the transformed individual item scores, divided by the number of non-missing items. Higher scores indicated better quality of life (fewer symptoms or problems). A scale score was only calculated if at least 50% of the associated items were non-missing. | Baseline and Week 12 |