Prospective, Multicenter, Randomized, Double-blind, Parallel-group, Dose-response Study of Three Doses Xeomin® (incobotulinumtoxinA, NT 201) for the Treatment of Upper Limb Spasticity Alone or Combined Upper and Lower Limb Spasticity in Children and Adolescents (Age 2 - 17 Years) With Cerebral Palsy
Overview
- Phase
- Phase 3
- Intervention
- IncobotulinumtoxinA (8 Units per kg body weight)
- Conditions
- Cerebral Palsy
- Sponsor
- Merz Pharmaceuticals GmbH
- Enrollment
- 351
- Locations
- 32
- Primary Endpoint
- MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
The purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of one or both arms alone or in combination with injections into one or both legs are effective and safe in treating children/adolescents (age 2-17 years) with increased muscle tension/uncontrollable muscle stiffness (spasticity) due to cerebral palsy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Female or male subject of 2 to 17 years of age (inclusive).
- •Uni- or bilateral Cerebral Palsy (CP) with clinical need for injections with NT 201 for the treatment of upper limb (UL) spasticity at least unilaterally.
- •Ashworth Scale (AS) score in the main clinical target patterns in this study:
- •Flexed elbow: AS≥2 in elbow flexors (at least unilaterally). and/or
- •Flexed Wrist: AS≥2 in wrist flexors (at least unilaterally).
- •Clinical need according to the judgment of the investigator in one out of five treatment combinations (A-E, as shown below). AS score must be ≥2 for each target pattern chosen for injection at the Baseline Injection Visit V
- •A. UL(s) treatment only (GMFCS I-V):
- •A1) Unilateral treatment of UL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) for:
- •At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).
- •Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.
Exclusion Criteria
- •Pre-treated (non-naïve) subjects must not have received BoNT treatment within the last 14 weeks prior to Screening Visit (V1) in any indication.
Arms & Interventions
8 Units per kg body weight incobotulinumtoxinA (Xeomin)
8 Units per kg body weight (maximum of 200 Units) will be injected per treated upper limb per injection cycle. Additionally, lower limb treatment may be administered, depending on clinical pattern: up to 300 Units per injection cycle. Overall maximum dose per injection cycle: 500 Units.
Intervention: IncobotulinumtoxinA (8 Units per kg body weight)
6 Units per kg body weight incobotulinumtoxinA (Xeomin)
6 Units per kg body weight (maximum of 150 Units) will be injected per treated upper limb per injection cycle. Additionally, lower limb treatment may be administered, depending on clinical pattern: up to 225 Units per injection cycle. Overall maximum dose per injection cycle: 375 Units.
Intervention: IncobotulinumtoxinA (6 Units per kg body weight)
2 Units per kg body weight incobotulinumtoxinA (Xeomin)
2 Units per kg body weight (maximum of 50 Units) will be injected per treated upper limb per injection cycle. Additionally, lower limb treatment may be administered, depending on clinical pattern: up to 75 Units per injection cycle. Overall maximum dose per injection cycle: 125 Units.
Intervention: IncobotulinumtoxinA (2 Units per kg body weight)
Outcomes
Primary Outcomes
MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4
Time Frame: Baseline and Week 4
The AS categorizes severity of spasticity by judging resistance to passive movement. Spasticity was assessed by using the 5-point AS with:0 (no increase in tone); 1 (slight increase in tone giving a "catch" when the limb was moved in flexion or extension); 2 (more marked increase in tone, but limb easily flexed); 3 (considerable increase in tone -passive movements difficult); 4 (limb rigid in flexion or extension). Values represent least square (LS) mean differences between baseline and Week 4 resulting from Mixed Model Repeated Measurement (MMRM) 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.
Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4
Time Frame: Week 4
The GICS was used to measure independently the investigator's impression of change due to treatment. The response option was a common 7-point Likert scale, that ranges from +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse). Values represent 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.
Secondary Outcomes
- MP: Change From Baseline in AS Score of the Other Treated UL Main Clinical Target Pattern at Week 4(Baseline and Week 4)
- MP: Change From Baseline in AS Score in UL Treated Clenched Fist With Flexed Wrist at Week 4(Baseline and Week 4)
- MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4(Baseline up to Week 4)
- MP: Change From Baseline in Scores of Pain Intensity (From Participants) and Pain Frequency (From Parent/Caregiver) Assessed With 'Questionnaire on Pain Caused by Spasticity (QPS)'(Baseline, Weeks 4, 8, and 14)
- Number of Participants With Occurrence of TEAEs of Special Interest (TEAESIs) Overall and Per Treatment Cycle(Baseline up to Week 66)
- Number of Participants With Occurrence of Serious TEAEs (TESAEs) Overall and Per Treatment Cycle(Baseline up to Week 66)
- Number of Participants With Occurrence of TEAEs Related to Treatment Overall and Per Treatment Cycle(Baseline up to Week 66)
- MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4(Week 4)
- Number of Participants With Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Treatment Cycle(Baseline up to Week 66)
- Number of Participants With Occurrence of TEAEs by Worst Intensity Overall and Per Treatment Cycle(Baseline up to Week 66)
- Number of Participants With Occurrence of TEAEs by Worst Causal Relationship Overall and Per Treatment Cycle(Baseline up to Week 66)
- Number of Participants With Occurrence of TEAEs by Final Outcome Overall and Per Treatment Cycle(Baseline up to Week 66)
- Number of Participants With Occurrence of TEAEs Leading to Discontinuation Overall and Per Treatment Cycle(Baseline up to Week 66)