Cerebral Palsy, Children, Muscle Spasticity
Conditions
Brief summary
The purpose of this research study is to determine whether Dysport® is effective in the treatment of increased stiffness of the calf muscles and to evaluate the safety of this treatment in children with Cerebral Palsy. In addition this study will also check whether Dysport® can lessen the pain caused by spasticity and improve the child's wellbeing.
Interventions
BIOLOGICALBotulinum toxin type A
I.M. (in the muscle) injection on day 1 of a single treatment cycle.
DRUGPlacebo
I.M. injection on day 1 of a single treatment cycle.
Sponsors
Ipsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Children aged 2 to 17 years with cerebral palsy * Equinus foot position * Ambulatory * Intensity of muscle tone equal to or greater than 2 in affected lower limb, as measured on the Modified Ashworth Scale
Exclusion criteria
* Fixed contracture * Previous phenol, alcohol injection or surgical intervention * Other neurological / neuromuscular disorder * Severe athetoid or dystonic movements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in MAS Score in the Gastrocnemius-soleus Complex (GSC) at the Ankle Joint of the (Most) Affected Lower Limb | Change from baseline to Week 4 | 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. Investigator will grade muscle tone in the GSC from 0 (no increase in tone) to 4 (affected parts rigid in flexion or extension). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Physician's Global Assessment (PGA) of the Treatment Response. | Week 4 | PGA Scale of the Treatment Response: Global assessment of treatment response 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 last injection? Answers will be 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). |
| Goal Attainment Scale (GAS) Score | Week 4 | GAS is a functional scale used to measure progress towards individual therapy goals. Individual goals defined for each subject by the physician, and the child's parents (caregiver) where applicable, prior to treatment. Post-baseline, the GAS for each goal 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). |
Countries
Chile, France, Mexico, Poland, Turkey (Türkiye), United States
Participant flow
Recruitment details
Each centre that participated in the study was expected to randomise between five and 25 subjects. It was planned to have at least two participating centres per country.
Pre-assignment details
Screening details: A total of 241 subjects were randomised to the study. The safety population included 239 subjects who were treated. Out of the 239 treated subjects, 4 subjects were excluded from the Intent-to-Treat (ITT) population because no MAS score was obtained at the baseline visit and/or at Week 4.
Participants by arm
| Arm | Count |
|---|---|
| Dysport 10 U/Kg Dysport 10 U/Kg intramuscular injection on either one or both lower limbs (2 ml per leg), single treatment. | 79 |
| Dysport 15 U/Kg Dysport 15 U/Kg intramuscular injection on either one or both lower limbs (2 ml per leg), single treatment. | 79 |
| Placebo Placebo intramuscular injection on either one or both lower limbs (2 ml per leg), single treatment. | 77 |
| Total | 235 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Randomised Population | No MAS score at baseline and/or Week 4 | 1 | 1 | 2 |
| Randomised Population | Study treatment not received | 0 | 0 | 2 |
| Treatment Phase - ITT Population | Adverse Event | 0 | 0 | 1 |
| Treatment Phase - ITT Population | Lost to Follow-up | 0 | 1 | 1 |
| Treatment Phase - ITT Population | Other | 0 | 0 | 1 |
| Treatment Phase - ITT Population | Withdrawal by Subject | 1 | 3 | 1 |
Baseline characteristics
| Characteristic | Dysport 10 U/Kg | Dysport 15 U/Kg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 6 years STANDARD_DEVIATION 3.3 | 5.7 years STANDARD_DEVIATION 3.2 | 5.9 years STANDARD_DEVIATION 3.5 | 5.9 years STANDARD_DEVIATION 3.3 |
| Age, Customized Children (10-17 years) | 12 participants | 12 participants | 12 participants | 36 participants |
| Age, Customized Children (2-9 years) | 67 participants | 67 participants | 65 participants | 199 participants |
| Body Mass Index (BMI) | 15.8 kg/m2 STANDARD_DEVIATION 2.9 | 16.1 kg/m2 STANDARD_DEVIATION 2.7 | 16.2 kg/m2 STANDARD_DEVIATION 2.7 | 16.0 kg/m2 STANDARD_DEVIATION 2.8 |
| Botulinum toxin Status Naive | 40 participants | 41 participants | 41 participants | 122 participants |
| Botulinum toxin Status Non-naive | 39 participants | 38 participants | 36 participants | 113 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 21 Participants | 21 Participants | 20 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 58 Participants | 57 Participants | 173 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Gross Motor Function Classification System (GMFCS) GMFCS level 1 | 46 participants | 45 participants | 40 participants | 131 participants |
| Gross Motor Function Classification System (GMFCS) GMFCS level 2 | 24 participants | 24 participants | 30 participants | 78 participants |
| Gross Motor Function Classification System (GMFCS) GMFCS level 3 | 9 participants | 10 participants | 7 participants | 26 participants |
| Height | 117.1 cm STANDARD_DEVIATION 20.7 | 111.6 cm STANDARD_DEVIATION 18.5 | 114.6 cm STANDARD_DEVIATION 19.7 | 114.4 cm STANDARD_DEVIATION 19.7 |
| Modified Ashworth Scale (MAS) score | 3.1 units on a scale STANDARD_DEVIATION 0.3 | 3.1 units on a scale STANDARD_DEVIATION 0.3 | 3.2 units on a scale STANDARD_DEVIATION 0.4 | 3.1 units on a scale STANDARD_DEVIATION 0.4 |
| Number of legs being treated 1 Leg injected | 42 participants | 50 participants | 47 participants | 139 participants |
| Number of legs being treated 2 Legs injected | 37 participants | 29 participants | 30 participants | 96 participants |
| Race/Ethnicity, Customized American Indian/Alaskan Native | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black/African American | 2 participants | 0 participants | 5 participants | 7 participants |
| Race/Ethnicity, Customized Caucasian/White | 57 participants | 60 participants | 55 participants | 172 participants |
| Race/Ethnicity, Customized Multiple | 19 participants | 19 participants | 17 participants | 55 participants |
| Sex: Female, Male Female | 45 Participants | 48 Participants | 48 Participants | 141 Participants |
| Sex: Female, Male Male | 34 Participants | 31 Participants | 29 Participants | 94 Participants |
| Weight | 23.1 kg STANDARD_DEVIATION 13.4 | 21.1 kg STANDARD_DEVIATION 10.7 | 22.6 kg STANDARD_DEVIATION 11.9 | 22.3 kg STANDARD_DEVIATION 12 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 51 / 80 | 51 / 80 | 42 / 79 |
| serious Total, serious adverse events | 1 / 80 | 0 / 80 | 4 / 79 |
Outcome results
Primary
Change in MAS Score in the Gastrocnemius-soleus Complex (GSC) at the Ankle Joint of the (Most) Affected Lower Limb
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. Investigator will grade muscle tone in the GSC from 0 (no increase in tone) to 4 (affected parts rigid in flexion or extension).
Time frame: Change from baseline to Week 4
Population: ITT population, defined as all randomised subjects who received at least one injection of study treatment and who had a MAS score in the GSC assessed both at baseline and at Week 4.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dysport 10 U/Kg | Change in MAS Score in the Gastrocnemius-soleus Complex (GSC) at the Ankle Joint of the (Most) Affected Lower Limb | -0.86 units on a scale |
| Dysport 15 U/Kg | Change in MAS Score in the Gastrocnemius-soleus Complex (GSC) at the Ankle Joint of the (Most) Affected Lower Limb | -0.97 units on a scale |
| Placebo | Change in MAS Score in the Gastrocnemius-soleus Complex (GSC) at the Ankle Joint of the (Most) Affected Lower Limb | -0.48 units on a scale |
Comparison: LS means for each treatment group and treatment comparisons, as well as the p-values were obtained from an ANCOVA on the change from baseline with treatment, baseline MAS score, age range at baseline, BTX status at baseline and centre as covariates.p-value: 0.002995% CI: [-0.64, -0.13]ANCOVA
Comparison: LS means for each treatment group and treatment comparisons, as well as the p-values were obtained from an ANCOVA on the change from baseline with treatment, baseline MAS score, age range at baseline, BTX status at baseline and centre as covariates.p-value: 0.000295% CI: [-0.75, -0.23]ANCOVA
Secondary
Goal Attainment Scale (GAS) Score
GAS is a functional scale used to measure progress towards individual therapy goals. Individual goals defined for each subject by the physician, and the child's parents (caregiver) where applicable, prior to treatment. Post-baseline, the GAS for each goal 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).
Time frame: Week 4
Population: ITT population, defined as all randomised subjects who received at least one injection of study treatment and who had a MAS score in the GSC assessed both at baseline and at Week 4.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dysport 10 U/Kg | Goal Attainment Scale (GAS) Score | 51.53 units on a scale |
| Dysport 15 U/Kg | Goal Attainment Scale (GAS) Score | 50.86 units on a scale |
| Placebo | Goal Attainment Scale (GAS) Score | 46.21 units on a scale |
Comparison: LS means for each treatment group and treatment comparisons, as well as the p-values were obtained from an ANOVA on the visit value with treatment, age range at baseline, BTX status at baseline and centre as covariates.p-value: 0.000695% CI: [2.31, 8.32]ANOVA
Comparison: LS means for each treatment group and treatment comparisons, as well as the p-values were obtained from an ANOVA on the visit value with treatment, age range at baseline, BTX status at baseline and centre as covariates.p-value: 0.003195% CI: [1.59, 7.71]ANOVA
Secondary
Physician's Global Assessment (PGA) of the Treatment Response.
PGA Scale of the Treatment Response: Global assessment of treatment response 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 last injection? Answers will be 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).
Time frame: Week 4
Population: ITT population, defined as all randomised subjects who received at least one injection of study treatment and who had a MAS score in the GSC assessed both at baseline and at Week 4.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dysport 10 U/Kg | Physician's Global Assessment (PGA) of the Treatment Response. | 1.54 units on a scale |
| Dysport 15 U/Kg | Physician's Global Assessment (PGA) of the Treatment Response. | 1.5 units on a scale |
| Placebo | Physician's Global Assessment (PGA) of the Treatment Response. | 0.73 units on a scale |
Comparison: LS means for each treatment group and treatment comparisons, as well as the p-values were obtained from an ANOVA on the visit value with treatment, age range at baseline, BTX status at baseline and centre as covariates.p-value: <0.000195% CI: [0.5, 1.14]ANOVA
Comparison: LS means for each treatment group and treatment comparisons, as well as the p-values were obtained from an ANOVA on the visit value with treatment, age range at baseline, BTX status at baseline and centre as covariates.p-value: <0.000195% CI: [0.45, 1.1]ANOVA