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
Overview
- Phase
- Phase 3
- Intervention
- IncobotulinumtoxinA (16 Units per kg body weight)
- Conditions
- Lower Limb Spasticity Due to Cerebral Palsy
- Sponsor
- Merz Pharmaceuticals GmbH
- Enrollment
- 311
- Locations
- 53
- Primary Endpoint
- 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)
- 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 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.
Investigators
Eligibility Criteria
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.
Arms & Interventions
16 Units per kg body weight incobotulinumtoxinA (Xeomin)
Intervention: IncobotulinumtoxinA (16 Units per kg body weight)
12 Units per kg body weight incobotulinumtoxinA (Xeomin)
Intervention: IncobotulinumtoxinA (12 Units per kg body weight)
4 Units per kg body weight incobotulinumtoxinA (Xeomin)
Intervention: IncobotulinumtoxinA (4 Units per kg body weight)
Outcomes
Primary Outcomes
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)
Time Frame: Baseline, Week 4
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.
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
Time Frame: Baseline, Week 4
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.
Secondary Outcomes
- Occurrence of Serious TEAEs (TESAEs) Overall and Per Injection Cycle(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(Up to End of study visit (Week 24-72))
- 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(Baseline to Week 8 and 12 of 1st IC and 2nd IC (Week 20-44 and 24-48))
- 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)(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(Baseline to Week 4 of 2nd IC (Week 16-40))
- 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(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(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(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(Up to End of study visit (Week 24-72))
- Occurrence of Participants With TEAEs of Special Interest (TEAESIs) Overall and Per Injection Cycle(Up to End of study visit (Week 24-72))
- 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(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(Baseline to Week 4, 8, and 12 of 1st IC and 2nd IC (Week 16-40, 20-44 and 24-48))
- 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(Baseline to Week 4 of 1st IC and 2nd IC (Week 16-40))
- Occurrence of TEAEs by Final Outcome Overall and Per Injection Cycle(Up to End of study visit (Week 24-72))
- Occurrence of TEAEs by Worst Intensity Overall and Per Injection Cycle(Up to End of study visit (Week 24-72))
- Occurrence of TEAEs Leading to Discontinuation Overall and Per Injection Cycle(Up to End of study visit (Week 24-72))