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

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02002884

Acronym

XARA

Enrollment

351

Registered

2013-12-06

Start date

2014-03-28

Completion date

2018-08-28

Last updated

2021-08-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cerebral Palsy, Spasticity

Keywords

Upper limb spasticity, lower limb spasticity, combined upper and lower limb spasticity

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.

Interventions

DRUGIncobotulinumtoxinA (8 Units per kg body weight)

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); Mode of administration: intramuscular injection into spastic muscles.

DRUGIncobotulinumtoxinA (6 Units per kg body weight)

DRUGIncobotulinumtoxinA (2 Units per kg body weight)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

2 Years to 17 Years

Healthy volunteers

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: 1. Flexed elbow: AS≥2 in elbow flexors (at least unilaterally). and/or 2. 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 V2. 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: 1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW). and 2. 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. or 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: 1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW). and 2. 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: 1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW). and 2. 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. plus 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: 1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW). and 2. 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. plus 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: 1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW). and 2. 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. plus 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 1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW) and 2. 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. plus 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.

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.

Design outcomes

Primary

Measure	Time frame	Description
MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4	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	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

Measure	Time frame	Description
Number of Participants With Occurrence of TEAEs Leading to Discontinuation Overall and Per Treatment Cycle	Baseline up to Week 66	—
MP: Change From Baseline in AS Score of the Other Treated UL Main Clinical Target Pattern at Week 4	Baseline and Week 4	The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 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 LS mean differences between baseline and Week 4 resulting from 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.
MP: Change From Baseline in AS Score in UL Treated Clenched Fist With Flexed Wrist at Week 4	Baseline and Week 4	The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 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 LS mean differences between baseline and Week 4 resulting from 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.
MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Baseline up to Week 4	The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 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 LS mean differences between baseline and Week 4 resulting from 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.
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	Pain intensity (from participants) and pain frequency (from parent/caregiver) to be assessed with 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 LS mean differences between baseline and Week 4 resulting from 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. P/C = Parent/Caregiver.
Number of Participants With Occurrence of TEAEs by Worst Causal Relationship 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	The GICS was used to measure independently the child's/adolescent's, and parent's or caregiver'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.
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 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	—
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 Final Outcome Overall and Per Treatment Cycle	Baseline up to Week 66	—

Countries

Argentina, Mexico, Poland, Russia, Ukraine, United States

Participant flow

Recruitment details

The study was conducted at 28 investigative sites in Mexico, Argentina, Russian federation, Ukraine, United States and Poland.

Pre-assignment details

A total of 372 participants were screened, 351 participants were randomized and 350 participants were randomized and treated in the study. 331 participants completed the main period (MP) and moved to the open-label-extension period (OLEX) out of which 281 participants completed the OLEX period.

Participants by arm

Arm	Count
MP Low Dose Group Participants in low dose group received intramuscular injections of 2 U/kg NT 201 (maximum of 50 U in participants with \>25 kg BW) into spastic muscles of one of the UL on Day 1 of MP. If the contralateral UL or one or both LL were also treated, participants received additional doses of NT 201. The total body dose ranged from 2 U/kg (50 U for participants with \>25kg BW) to 5 U/kg (125 U for participants with \>25kg BW) depending on the combination of treated limbs and the participant's GMFCS level.	87
MP Mid Dose Group Participants in mid dose group received intramuscular injections of 6 U/kg NT 201 (maximum of 150 U in participants with \>25kg BW) into spastic muscles of one of the UL on Day 1 of MP. If the contralateral UL or one or both LL were also treated, participants received additional doses of NT 201. The total body dose ranged from 6 U/kg (150 U for participants with \>25kg BW) to 15 U/kg (375 U for participants with \>25kg BW) depending on the combination of treated limbs and the participant's GMFCS level.	88
MP High Dose Group Participants in high dose group received intramuscular injections of 8 U/kg NT 201 (maximum of 200 U in participants with \>25kg BW) into spastic muscles of one of the UL on Day 1 of MP. If the contralateral UL or one or both LL were also treated, participants received additional doses of NT 201. The total body dose ranged from 8 U/kg (200 U for participants with \>25kg BW) to 20 U/kg (500 U for participants with \>25kg BW) depending on the combination of treated limbs and the participant's GMFCS level.	176
Total	351

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Main Period (MP)	Adverse Event	0	1	1	0
Main Period (MP)	Lost to Follow-up	0	0	2	0
Main Period (MP)	Other	0	3	3	0
Main Period (MP)	Withdrawal by Subject	6	2	2	0
Open-Label Extension Period (OLEX)	Adverse Event	0	0	0	5
Open-Label Extension Period (OLEX)	Lost to Follow-up	0	0	0	10
Open-Label Extension Period (OLEX)	Other	0	0	0	24
Open-Label Extension Period (OLEX)	Physician Decision	0	0	0	1
Open-Label Extension Period (OLEX)	Withdrawal by Subject	0	0	0	10

Baseline characteristics

Characteristic	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group	Total
Age, Continuous	7.2 Years STANDARD_DEVIATION 4.7	7.4 Years STANDARD_DEVIATION 4.13	7.3 Years STANDARD_DEVIATION 4.4	7.3 Years STANDARD_DEVIATION 4.4
Race/Ethnicity, Customized Black or African American	3 Participants	2 Participants	2 Participants	7 Participants
Race/Ethnicity, Customized Hispanic or Latino	16 Participants	26 Participants	45 Participants	87 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	71 Participants	62 Participants	131 Participants	264 Participants
Race/Ethnicity, Customized Other	3 Participants	11 Participants	14 Participants	28 Participants
Race/Ethnicity, Customized White	81 Participants	75 Participants	160 Participants	316 Participants
Sex: Female, Male Female	38 Participants	31 Participants	62 Participants	131 Participants
Sex: Female, Male Male	49 Participants	57 Participants	114 Participants	220 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 87	0 / 87	0 / 176	0 / 331
other Total, other adverse events	5 / 87	3 / 87	6 / 176	18 / 331
serious Total, serious adverse events	2 / 87	1 / 87	2 / 176	16 / 331

Outcome results

Primary

Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at 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.

Time frame: Week 4

Population: The FAS was the subset in the SES of the MP for whom the primary efficacy variable or co-primary efficacy variable were available (that is, all participants who had at least an AS score in clinical pattern flexed elbow or flexed wrist at baseline \[Day 1\] or Investigator's GICS at Day 29 \[Week 4\]).

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
MP Low Dose Group	Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4	High versus low	1.55 Unit on a scale	Standard Error 0.083
MP Low Dose Group	Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4	Mid versus low	1.57 Unit on a scale	Standard Error 0.089
MP Mid Dose Group	Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4	Mid versus low	1.44 Unit on a scale	Standard Error 0.092
MP High Dose Group	Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4	High versus low	1.64 Unit on a scale	Standard Error 0.062

Comparison: LS-Means are from analysis of covariance (ANCOVA) with treatment group, pooled site and pretreatment status included as fixed factors and maximum AS score of the two possible primary target patterns flexed elbow or flexed wrist baseline, GMFCS-E\&R level at screening included as covariates.p-value: =0.3495% CI: [-0.1, 0.28]ANCOVA

Comparison: LS-Means are from ANCOVA with treatment group, pooled site and pre-treatment status included as fixed factors and maximum AS score of the two possible primary target patterns flexed elbow or flexed wrist baseline, GMFCS-E\&R level at screening included as covariates.p-value: =0.29795% CI: [-0.36, 0.11]ANCOVA

Primary

MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at 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.

Time frame: Baseline and Week 4

Population: The full analysis set (FAS) was the subset in the safety evaluation set (SES) of the MP for whom the primary efficacy variable or co-primary efficacy variable were available. Number of participants who were evaluable for this measure at a given time period and were included in the assessment.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
MP Low Dose Group	MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4	High versus low	-0.93 Unit on a scale	Standard Error 0.078
MP Low Dose Group	MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4	Mid versus low	-0.96 Unit on a scale	Standard Error 0.082
MP Mid Dose Group	MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4	Mid versus low	-1.02 Unit on a scale	Standard Error 0.082
MP High Dose Group	MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4	High versus low	-1.15 Unit on a scale	Standard Error 0.056

Comparison: LS-Means are from mixed model with treatment group, pooled site and pre-treatment status included as fixed factors and AS at baseline, Gross Motor Function Classification System-Extended and Revised (GMFCS-E\&R) level at screening included as covariates. For MMRM visit\*treatment is interaction term repeated factor.p-value: =0.01795% CI: [-0.4, -0.04]MMRM

Comparison: LS-Means are from mixed model with treatment group, pooled site and pre-treatment status included as fixed factors and AS at baseline, GMFCS-E\&R level at screening included as covariates. For MMRM visit\*treatment is interaction term repeated factor.p-value: =0.54695% CI: [-0.29, 0.15]MMRM

Secondary

MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4

The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 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 LS mean differences between baseline and Week 4 resulting from 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.

Time frame: Baseline up to Week 4

Population: The FAS was the subset in the SES of the MP for whom the primary efficacy variable or co-primary efficacy variable were available. Number of participants who were evaluable for this measure at a given time period and were included in the assessment.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
MP Low Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Clenched fist: Mid versus Low	-0.58 Unit on a scale	Standard Error 0.145
MP Low Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Flexed elbow: Mid versus Low	-1.01 Unit on a scale	Standard Error 0.081
MP Low Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Thumb in palm: High versus Low	-0.88 Unit on a scale	Standard Error 0.116
MP Low Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Thumb in palm: Mid versus Low	-0.93 Unit on a scale	Standard Error 0.131
MP Low Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Flexed elbow: High versus Low	-0.99 Unit on a scale	Standard Error 0.076
MP Low Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Flexed wrist: High versus Low	-0.96 Unit on a scale	Standard Error 0.085
MP Low Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Flexed wrist: Mid versus Low	-1.01 Unit on a scale	Standard Error 0.087
MP Low Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Pronated forearm: Mid versus Low	-0.87 Unit on a scale	Standard Error 0.086
MP Low Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Clenched fist: High versus Low	-0.64 Unit on a scale	Standard Error 0.136
MP Low Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Pronated forearm: High versus Low	-0.88 Unit on a scale	Standard Error 0.08
MP Mid Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Pronated forearm: Mid versus Low	-0.94 Unit on a scale	Standard Error 0.088
MP Mid Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Flexed elbow: Mid versus Low	-1.17 Unit on a scale	Standard Error 0.082
MP Mid Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Flexed wrist: Mid versus Low	-1.05 Unit on a scale	Standard Error 0.087
MP Mid Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Clenched fist: Mid versus Low	-0.87 Unit on a scale	Standard Error 0.141
MP Mid Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Thumb in palm: Mid versus Low	-1.14 Unit on a scale	Standard Error 0.123
MP High Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Flexed wrist: High versus Low	-1.08 Unit on a scale	Standard Error 0.061
MP High Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Clenched fist: High versus Low	-1.09 Unit on a scale	Standard Error 0.096
MP High Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Pronated forearm: High versus Low	-1.02 Unit on a scale	Standard Error 0.058
MP High Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Flexed elbow: High versus Low	-1.18 Unit on a scale	Standard Error 0.056
MP High Dose Group	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	Thumb in palm: High versus Low	-1.11 Unit on a scale	Standard Error 0.083

Secondary

MP: Change From Baseline in AS Score in UL Treated Clenched Fist With Flexed Wrist at Week 4

Time frame: Baseline and Week 4

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
MP Low Dose Group	MP: Change From Baseline in AS Score in UL Treated Clenched Fist With Flexed Wrist at Week 4	High versus low	-0.53 Unit on a scale	Standard Error 0.212
MP Low Dose Group	MP: Change From Baseline in AS Score in UL Treated Clenched Fist With Flexed Wrist at Week 4	Mid versus low	-0.070 Unit on a scale	Standard Error 0.202
MP Mid Dose Group	MP: Change From Baseline in AS Score in UL Treated Clenched Fist With Flexed Wrist at Week 4	Mid versus low	-1.04 Unit on a scale	Standard Error 0.176
MP High Dose Group	MP: Change From Baseline in AS Score in UL Treated Clenched Fist With Flexed Wrist at Week 4	High versus low	-1.00 Unit on a scale	Standard Error 0.133

Secondary

MP: Change From Baseline in AS Score of the Other Treated UL Main Clinical Target Pattern at Week 4

Time frame: Baseline and Week 4

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
MP Low Dose Group	MP: Change From Baseline in AS Score of the Other Treated UL Main Clinical Target Pattern at Week 4	High versus low	-1.03 Unit on a scale	Standard Error 0.083
MP Low Dose Group	MP: Change From Baseline in AS Score of the Other Treated UL Main Clinical Target Pattern at Week 4	Mid versus low	-1.08 Unit on a scale	Standard Error 0.087
MP Mid Dose Group	MP: Change From Baseline in AS Score of the Other Treated UL Main Clinical Target Pattern at Week 4	Mid versus low	-1.22 Unit on a scale	Standard Error 0.09
MP High Dose Group	MP: Change From Baseline in AS Score of the Other Treated UL Main Clinical Target Pattern at Week 4	High versus low	-1.13 Unit on a scale	Standard Error 0.061

Secondary

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)'

Pain intensity (from participants) and pain frequency (from parent/caregiver) to be assessed with 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 LS mean differences between baseline and Week 4 resulting from 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. P/C = Parent/Caregiver.

Time frame: Baseline, Weeks 4, 8, and 14

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
MP Low Dose Group	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)'	UL, P/C, Week 4 High versus low	-0.46 Unit on a scale	Standard Error 0.102
MP Low Dose Group	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)'	UL, Participant, Week 4 Mid versus low	-0.39 Unit on a scale	Standard Error 0.256
MP Low Dose Group	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)'	UL, Participant, Week 8 High versus low	-0.52 Unit on a scale	Standard Error 0.206
MP Low Dose Group	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)'	UL, Participant, Week 8 Mid versus low	-0.63 Unit on a scale	Standard Error 0.259
MP Low Dose Group	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)'	UL, Participant, Week 14 High versus low	-0.56 Unit on a scale	Standard Error 0.217
MP Low Dose Group	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)'	UL, Participant, Week 14 Mid versus low	-0.66 Unit on a scale	Standard Error 0.327
MP Low Dose Group	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)'	UL, Participant, Week 4 High versus low	-0.42 Unit on a scale	Standard Error 0.217
MP Low Dose Group	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)'	UL, P/C, Week 4 Mid versus low	-0.43 Unit on a scale	Standard Error 0.106
MP Low Dose Group	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)'	UL, P/C, Week 8 High versus low	-0.40 Unit on a scale	Standard Error 0.095
MP Low Dose Group	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)'	UL, P/C, Week 8 Mid versus low	-0.43 Unit on a scale	Standard Error 0.1
MP Low Dose Group	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)'	UL, P/C, Week 14 High versus Low	-0.23 Unit on a scale	Standard Error 0.105
MP Low Dose Group	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)'	UL, P/C, Week 14 Mid versus Low	-0.31 Unit on a scale	Standard Error 0.1
MP Low Dose Group	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)'	LL, Participant, Week 4 High versus Low	-0.74 Unit on a scale	Standard Error 0.282
MP Low Dose Group	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)'	LL, Participant, Week 4 Mid versus Low	-0.46 Unit on a scale	Standard Error 0.305
MP Low Dose Group	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)'	LL, Participant, Week 8 High versus Low	-1.04 Unit on a scale	Standard Error 0.241
MP Low Dose Group	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)'	LL, Participant, Week 8 Mid versus Low	-0.90 Unit on a scale	Standard Error 0.261
MP Low Dose Group	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)'	LL, Participant, Week 14 High versus Low	-0.71 Unit on a scale	Standard Error 0.275
MP Low Dose Group	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)'	LL, Participant, Week 14 Mid versus Low	-0.67 Unit on a scale	Standard Error 0.315
MP Low Dose Group	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)'	LL, P/C, Week 4 High versus Low	-0.50 Unit on a scale	Standard Error 0.105
MP Low Dose Group	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)'	LL, P/C, Week 4 Mid versus Low	-0.46 Unit on a scale	Standard Error 0.103
MP Low Dose Group	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)'	LL, P/C, Week 8 High versus Low	-0.56 Unit on a scale	Standard Error 0.098
MP Low Dose Group	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)'	LL, P/C, Week 8 Mid versus Low	-0.52 Unit on a scale	Standard Error 0.102
MP Low Dose Group	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)'	LL, P/C, Week 14 High versus Low	-0.33 Unit on a scale	Standard Error 0.108
MP Low Dose Group	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)'	LL, P/C, Week 14 Mid versus Low	-0.37 Unit on a scale	Standard Error 0.086
MP Mid Dose Group	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)'	UL, P/C, Week 14 Mid versus Low	-0.25 Unit on a scale	Standard Error 0.107
MP Mid Dose Group	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)'	UL, Participant, Week 4 Mid versus low	-0.67 Unit on a scale	Standard Error 0.289
MP Mid Dose Group	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)'	LL, Participant, Week 4 Mid versus Low	-0.55 Unit on a scale	Standard Error 0.321
MP Mid Dose Group	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)'	UL, Participant, Week 8 Mid versus low	-0.55 Unit on a scale	Standard Error 0.29
MP Mid Dose Group	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)'	LL, P/C, Week 8 Mid versus Low	-0.36 Unit on a scale	Standard Error 0.111
MP Mid Dose Group	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)'	UL, Participant, Week 14 Mid versus low	-0.59 Unit on a scale	Standard Error 0.361
MP Mid Dose Group	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)'	LL, P/C, Week 4 Mid versus Low	-0.42 Unit on a scale	Standard Error 0.111
MP Mid Dose Group	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)'	LL, Participant, Week 8 Mid versus Low	-0.81 Unit on a scale	Standard Error 0.284
MP Mid Dose Group	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)'	UL, P/C, Week 4 Mid versus low	-0.28 Unit on a scale	Standard Error 0.115
MP Mid Dose Group	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)'	LL, P/C, Week 14 Mid versus Low	-0.31 Unit on a scale	Standard Error 0.09
MP Mid Dose Group	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)'	UL, P/C, Week 8 Mid versus low	-0.34 Unit on a scale	Standard Error 0.109
MP Mid Dose Group	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)'	LL, Participant, Week 14 Mid versus Low	-0.63 Unit on a scale	Standard Error 0.335
MP High Dose Group	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)'	LL, Participant, Week 14 High versus Low	-0.57 Unit on a scale	Standard Error 0.245
MP High Dose Group	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)'	UL, Participant, Week 4 High versus low	-0.75 Unit on a scale	Standard Error 0.199
MP High Dose Group	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)'	LL, Participant, Week 4 High versus Low	-0.62 Unit on a scale	Standard Error 0.25
MP High Dose Group	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)'	UL, P/C, Week 4 High versus low	-0.44 Unit on a scale	Standard Error 0.076
MP High Dose Group	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)'	LL, P/C, Week 4 High versus Low	-0.52 Unit on a scale	Standard Error 0.077
MP High Dose Group	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)'	UL, Participant, Week 8 High versus low	-0.64 Unit on a scale	Standard Error 0.188
MP High Dose Group	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)'	LL, P/C, Week 14 High versus Low	-0.32 Unit on a scale	Standard Error 0.078
MP High Dose Group	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)'	LL, P/C, Week 8 High versus Low	-0.51 Unit on a scale	Standard Error 0.074
MP High Dose Group	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)'	UL, P/C, Week 14 High versus Low	-0.24 Unit on a scale	Standard Error 0.071
MP High Dose Group	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)'	UL, Participant, Week 14 High versus low	-0.59 Unit on a scale	Standard Error 0.202
MP High Dose Group	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)'	LL, Participant, Week 8 High versus Low	-0.69 Unit on a scale	Standard Error 0.218
MP High Dose Group	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)'	UL, P/C, Week 8 High versus low	-0.44 Unit on a scale	Standard Error 0.07

Secondary

MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4

The GICS was used to measure independently the child's/adolescent's, and parent's or caregiver'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.

Time frame: Week 4

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
MP Low Dose Group	MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4	Participant: High versus Low	1.51 Unit on a scale	Standard Error 0.153
MP Low Dose Group	MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4	Participant: Mid versus Low	1.53 Unit on a scale	Standard Error 0.18
MP Low Dose Group	MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4	Parent/Caregiver: High versus Low	1.41 Unit on a scale	Standard Error 0.087
MP Low Dose Group	MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4	Parent/Caregiver: Mid versus Low	1.36 Unit on a scale	Standard Error 0.094
MP Mid Dose Group	MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4	Parent/Caregiver: Mid versus Low	1.29 Unit on a scale	Standard Error 0.097
MP Mid Dose Group	MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4	Participant: Mid versus Low	1.48 Unit on a scale	Standard Error 0.19
MP High Dose Group	MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4	Participant: High versus Low	1.63 Unit on a scale	Standard Error 0.139
MP High Dose Group	MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4	Parent/Caregiver: High versus Low	1.60 Unit on a scale	Standard Error 0.065

Secondary