Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Leg(s) in Cerebral Palsy

Study Overview
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Brief Summary
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The purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of the leg(s) are effective in treating children/adolescents (age 2-17 years) with increased muscle tension/uncontrollable muscle stiffness (spasticity) due to cerebral palsy.

Official Title
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Prospective, Multicenter, Randomized, Double-blind, Parallel-group, Dose-response Study of Three Doses Xeomin® (incobotulinumtoxinA, NT 201) for the Treatment of Lower Limb Spasticity in Children and Adolescents (Age 2 - 17 Years) With Cerebral Palsy

Conditions
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Lower Limb Spasticity Due to Cerebral Palsy

Intervention / Treatment
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* Drug: IncobotulinumtoxinA (16 Units per kg body weight)
* Drug: IncobotulinumtoxinA (12 Units per kg body weight)
* Drug: IncobotulinumtoxinA (4 Units per kg body weight)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male subject of 2 to 17 years of age (inclusive). Uni- or bilateral cerebral palsy with clinical need for uni- or bilateral LL injections with BoNT for the treatment of spasticity. Ashworth Scale [AS] score ≥2 in plantar flexors (at least unilaterally). Clinical need for a total dose of 16 U/kg BW NT 201 (maximum of 400 U) for the treatment of LL spasticity according to the clinical judgment of the investigator. Exclusion Criteria: Fixed contracture defined as severe restriction of the range of joint movement on passive stretch or predominant forms of muscle hypertonia other than spasticity (e.g., dystonia) in the target limb(s). Surgery on pes equinus on side(s) intended to be treated with BoNT injections in this study within 12 months prior to Screening Visit (V1), in the screening period or planned for the time of participation in this study. Hip flexion requiring BoNT injection.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 16 Units per kg body weight incobotulinumtoxinA (Xeomin)<br> | Drug: IncobotulinumtoxinA (16 Units per kg body weight)<br>* Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Total volume 8.0 mL; 400 units; Mode of administration: intramuscular injection into spastic muscles.<br>* Other names: Botulinum toxin type A (150 kiloDalton), free from complexing proteins;|
| Experimental: 12 Units per kg body weight incobotulinumtoxinA (Xeomin)<br> | Drug: IncobotulinumtoxinA (12 Units per kg body weight)<br>* Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Total volume 8.0 mL; 300 units; Mode of administration: intramuscular injection into spastic muscles.<br>* Other names: Botulinum toxin type A (150 kiloDalton), free from complexing proteins;|
| Experimental: 4 Units per kg body weight incobotulinumtoxinA (Xeomin)<br> | Drug: IncobotulinumtoxinA (4 Units per kg body weight)<br>* Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Total volume 8.0 mL; 100 units; Mode of administration: intramuscular injection into spastic muscles.<br>* Other names: Botulinum toxin type A (150 kiloDalton), free from complexing proteins;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Ashworth Scale (AS) Score of Plantar Flexors of the Primary Body Side at Day 29 (Week 4) of the First Injection Cycle (1st IC) | The Ashworth Scale (AS) is a well known and commonly used scale in clinical trials with spasticity. In spastic muscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (= no increase in tone) to 4 (=limb rigid in flexion or extension). For participants with bilateral pes equinus, the body side for primary efficacy analysis i.e. primary body side was decided by investigator at screening and was kept throughout the entire study. For participants with unilateral treatment, the treated body side was kept throughout the entire study. Values represent least square (LS) mean differences between baseline and Week 4 resulting from MMRM (Mixed Model Repeated Measurement) models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. | Baseline, Week 4 | 
| Co-primary Variable: Investigator's Global Impression of Change of Plantar Flexor Spasticity Scale (GICS-PF) of the Primary Body Side at Day 29 (Week 4) of the First Injection Cycle | This variable is classified as co-primary to satisfy a Food and Drug Administration (FDA) request. The GICS-PF scale is a 7-Point Likert Scale for the assessment of the functional change due to treatment of plantar flexor spasticity only. Ranges from +3 (very much improved function) to -3 (very much worse function). For participants with bilateral pes equinus, the body side for primary efficacy analysis i.e. primary body side was decided by investigator at screening and was kept throughout the entire study. For participants with unilateral treatment, the treated body side was kept throughout the entire study. Values represent least square (LS) mean differences between baseline and Week 4 resulting from ANCOVA models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. | Baseline, Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the AS Score of Plantar Flexors of the Nonprimary Body Side in Participants With Bilateral Treatment at Day 29 (Week 4) of the First (1st) and Second Injection Cycle (2nd IC) | The Ashworth Scale (AS) is a well known and commonly used scale in clinical trials with spasticity. In spastic muscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). Values represent least square (LS) mean differences between baseline and the respective week (w) resulting from MMRM (Mixed Model Repeated Measurement) models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. | Baseline, Week 4 of 1st IC and Week 16-40 of 2nd IC | 
| Change From Baseline in the AS Score of Plantar Flexors of the Primary Body Side at Day 29 (Week 4) of the Second Injection Cycle | The Ashworth Scale (AS) is a well known and commonly used scale in clinical trials with spasticity. In spastic muscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). For participants with bilateral pes equinus, the body side for primary efficacy analysis i.e. primary body side was decided by investigator at screening and was kept throughout the entire study. For participants with unilateral treatment, the treated body side was kept throughout the entire study. Values represent least square (LS) mean differences between baseline and Week 16-40 resulting from MMRM (Mixed Model Repeated Measurement) models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. | Baseline to Week 4 of 2nd IC (Week 16-40) | 
| Changes From Baseline in AS Score of Plantar Flexors of the Primary Body Side at Day 57 (Week 8) and Day 85 (Week 12) of the First and of the Second Injection Cycle | The Ashworth Scale (AS) is a well known and commonly used scale in clinical trials with spasticity. In spastic muscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). For participants with bilateral pes equinus, the body side for primary efficacy analysis i.e. primary body side was decided by investigator at screening and was kept throughout the entire study. For participants with unilateral treatment, the treated body side was kept throughout the entire study. Values represent least square (LS) mean differences between baseline and the respective week (w) resulting from MMRM (Mixed Model Repeated Measurement) models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. | Baseline to Week 8 and 12 of 1st IC and 2nd IC (Week 20-44 and 24-48) | 
| Changes From Baseline in AS Score of Knee Flexors or Thigh Adductors in Participants With Unilateral Treatment at Day 29 (Week 4) of the First and of the Second Injection Cycle | The Ashworth Scale (AS) is a well known and commonly used scale in clinical trials with spasticity. In spastic muscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension). Values represent least square (LS) mean differences between baseline and the respective week (w) resulting from MMRM (Mixed Model Repeated Measurement) models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. KF = Knee Flexors; TA = Thigh Adductors; w = week. | Baseline to Week 4 of 1st IC and 2nd IC (Week 16-40) | 
| Changes From Baseline in Modified Tardieu Scale [MTS] of Plantar Flexors of Primary Body Side at Day 29 (Week 4), Day 57 (Week 8), and Day 85 (Week 12) of the First and of the Second Injection Cycle | The Modified Tardieu Scale (MTS) assesses spastic muscle tone by subtraction of two angles measured at different conditions of passive muscle stretch. R2 is the angle of passive range of motion with a passive movement at slow speed. R1 is the angle where a catch-and-release or clonus can be triggered at the fastest possible speed. Score values represent the measured (R2-R1) difference, i.e. the dynamic tone component of the examined muscle(s). Decreases of (R2-R1) represent reductions in the dynamic component of spasticity, i.e. improvement of dynamic muscle spasticity. Values represent least square (LS) mean differences between baseline and the respective week (w) resulting from ANCOVA models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the model used for comparison and are therefore provided separately for each comparison. | Baseline to Week 4, 8, and 12 of 1st IC and 2nd IC (Week 16-40, 20-44 and 24-48) | 
| Investigator's, Child's/Adolescent's, and Parent's/Caregiver's Global Impression of Change Scale [GICS] at Day 29 (Week 4) of the First and Second Injection Cycle | The Global Impression of Change Scales (GICS) are global outcomes to assess the impression of change due to treatment. GICS were assessed by the investigator, by the participant (if feasible) and by parents'/caregiver (if applicable). GICS are 7-Point Likert Scales ranging from +3 (very much improved function) to -3 (very much worse function). Values represent least square (LS) mean differences between baseline and the respective week (w) resulting from MMRM (Mixed Model Repeated Measurement) models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. | Baseline to Week 4 of 1st IC and 2nd IC (Week 16-40) | 
| Investigator's Global Impression of Change of GICS-Plantar-Flexor of Primary Body Side at Day 29 (Week 4) of the First and Second Injection Cycle | The GICS are global outcomes to assess the impression of change due to treatment. GICS were assessed by the investigator, by the participant (if feasible) and by parents'/caregiver (if applicable). GICS are 7-Point Likert Scales ranging from +3 (very much improved function) to -3 (very much worse function). For participants with bilateral pes equinus, the body side for primary efficacy analysis i.e. primary body side was decided by investigator at screening and was kept throughout the entire study. For participants with unilateral treatment, the treated body side was kept throughout the entire study. Values represent least square (LS) mean differences between baseline and the respective week (w) resulting from ANCOVA models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. | Baseline to Week 4 of 1st IC and 2nd IC (Week 16-40) | 
| Changes From Baseline in Gross Motor Function Measure [GMFM]-66 Score at the End of First Injection Cycle and at the End of Study Visit | The GMFM-66 is a standardized observational 66-item instrument designed and validated to measure change in gross motor function over time in participants with cerebral palsy. Score values represent the total GMFM-66 score. Total GMFM scores range from 0 (worst) to 100 (best). Values represent least square (LS) mean differences between baseline and the respective week (w) resulting from ANCOVA models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. | Baseline to Week 12-36 of 1st IC and 2nd IC (End of study = Week 24-72) | 
| Change in Scores of Pain Intensity (From Participants) and Pain Frequency (From Parent/Caregiver) to All Post Baseline Visits of the First and of the Second Injection Cycle | The QPS is a patient-reported outcome for children and adolescents (2-17 years) with cerebral palsy on spasticity-related pain. Pain intensity (from participants) and pain frequency (from parent/caregiver) to be assessed with 'Questionnaire on Pain caused by Spasticity [QPS]'. The QPS Total Score for pain intensity ranges from 0 ('No Hurt') to 10 ('Hurt Worst'). The QPS Total Score for the observed pain frequency ranges from 0 (Never) to 4 (Always). Values represent least square (LS) mean differences between baseline and the respective week (w) resulting from ANCOVA models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. | Baseline to Week 4, 8, and 12 of 1st IC and 2nd IC (Week 16-40, 20-44 and 24-48) | 
| Time to Reinjection for Each of the Three Dose Groups for the First and Second Injection Cycle |  | Baseline up to Week 24-72 | 
| Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Injection Cycle | Treatment-emergent Adverse Events (TEAEs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of participants affected. | Up to End of study visit (Week 24-72) | 
| Occurrence of Participants With TEAEs of Special Interest (TEAESIs) Overall and Per Injection Cycle | Adverse Events (AE's) occurring after treatment that were thought to possibly indicate toxin spread throughout the trial conduct are defined as AE's of Special Interests. Values reported here refer to the number of participants affected. | Up to End of study visit (Week 24-72) | 
| Occurrence of Serious TEAEs (TESAEs) Overall and Per Injection Cycle | Treatment-emergent Serious Adverse Events (TESAEs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of participants affected. | Up to End of study visit (Week 24-72) | 
| Occurrence of TEAEs Related to Treatment as Assessed by the Investigator Overall and Per Injection Cycle | Treatment-emergent Adverse Events (TEAEs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of participants affected. | Up to End of study visit (Week 24-72) | 
| Occurrence of TEAEs by Worst Intensity Overall and Per Injection Cycle | Treatment-emergent Adverse Events (TEAEs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of participants affected. | Up to End of study visit (Week 24-72) | 
| Occurrence of TEAEs by Final Outcome Overall and Per Injection Cycle | Treatment-emergent Adverse Events (TEAEs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of participants affected. | Up to End of study visit (Week 24-72) | 
| Occurrence of TEAEs Leading to Discontinuation Overall and Per Injection Cycle | Treatment-emergent Adverse Events (TEASs) are events observed from the time point of first injection until end of study visit (week 24-72). Values reported here refer to the number of participants affected. | Up to End of study visit (Week 24-72) |