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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 351
- 试验地点
- 32
- 主要终点
- MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 2 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •A2) Bilateral treatment of UL spasticity with equal doses of 8 U/kg BW NT 201 (maximum of 200 U) to each UL. Dose per UL must be distributed between:
- •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.
- •B. Unilateral UL and unilateral lower limb (LL) treatment (GMFCS I-V):
- •B1) 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.
- •B2) Ipsilateral unilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U). Dose to LL must be distributed to at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe as clinically needed.
- •C. Unilateral UL and bilateral LL treatment (GMFCS I-III)
- •C1) 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.
- •C2) Bilateral treatment of LL spasticity with 12 U/kg BW (maximum of 300 U). Dose must be distributed into at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe, on each side. Dose distribution may vary between sides as clinically needed.
- •D. Unilateral UL and bilateral LL treatment (GMFCS IV and V)
- •D1) 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.
- •D2) Bilateral treatment of LL spasticity with 8 U/kg BW (maximum of 200 U). Dose must be distributed into at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe, on each side. Dose distribution may vary between sides as clinically needed.
- •E. Bilateral UL treatment and bilateral LL treatment (GMFCS I-III)
- •E1) Bilateral treatment of UL spasticity with equal doses of 8 U/kg BW NT 201 (maximum of 200 U) to each UL. Dose per UL must be distributed between
- •At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW) and
- •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.
- •E2) Bilateral treatment of LL spasticity with 4 U/kg BW (maximum of 100 U). Dose must be distributed into at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe, on each side. Dose distribution may vary between sides as clinically needed.
排除标准
- •Pre-treated (non-naïve) subjects must not have received BoNT treatment within the last 14 weeks prior to Screening Visit (V1) in any indication.
研究组 & 干预措施
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.
干预措施: IncobotulinumtoxinA (8 Units per kg body weight) (Drug)
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.
干预措施: IncobotulinumtoxinA (6 Units per kg body weight) (Drug)
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.
干预措施: IncobotulinumtoxinA (2 Units per kg body weight) (Drug)
结局指标
主要结局
MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4
时间窗: 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
时间窗: 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.
次要结局
- 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)