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Clinical Trial Results:
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

Summary
EudraCT number	2012-005054-30
Trial protocol	EE AT DE SK CZ ES Outside EU/EEA FR
Global end of trial date	11 May 2016

Results information
Results version number	v2(current)
This version publication date	18 Aug 2017
First version publication date	24 Nov 2016
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

MRZ60201_3070_1

ISRCTN number

US NCT number

NCT01893411

WHO universal trial number (UTN)

Sponsor organisation name

Merz Pharmaceuticals GmbH

Sponsor organisation address

Eckenheimer Landstrasse 100, Frankfurt/M, Germany, 60318

Public contact

Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 69 1503 1, clinicaltrials@merz.de

Scientific contact

Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 69 1503 1, clinicaltrials@merz.de

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001039-PIP01-10

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Jun 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

11 May 2016

Was the trial ended prematurely?

Main objective of the trial

The main objective of the study was to investigate the dose-response of Botulinum neurotoxin type A free from complexing proteins (NT 201) in subjects with Lower limb (LL) spasticity due toCerebral palsy (CP) after injection treatment in three parallel dose groups: 16 Units [U]/kg body weight [BW] NT 201 with a maximum total dose of 400 U in the high dose group, 12 U/kg BW NT 201 with a maximum total dose of 300 U in the mid dose group, and 4 U/kg BW NT 201 with a maximum total dose of 100 U in the low dose group. Two injection treatments were followed by 12 to 36 weeks observation each (overall duration: 24-72 weeks).

Protection of trial subjects

High medical and ethical standards were followed in accordance with Good Clinical Practice and other applicable regulations. In addition, an independent data monitoring committee was in charge of monitoring patient safety while the study was ongoing.

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Jul 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 61

Country: Number of subjects enrolled

Slovakia: 14

Country: Number of subjects enrolled

Spain: 5

Country: Number of subjects enrolled

Austria: 8

Country: Number of subjects enrolled

Czech Republic: 5

Country: Number of subjects enrolled

Estonia: 4

Country: Number of subjects enrolled

France: 1

Country: Number of subjects enrolled

Germany: 6

Country: Number of subjects enrolled

Israel: 1

Country: Number of subjects enrolled

Turkey: 10

Country: Number of subjects enrolled

Russian Federation: 26

Country: Number of subjects enrolled

Ukraine: 107

Country: Number of subjects enrolled

Korea, Republic of: 54

Country: Number of subjects enrolled

Romania: 9

Worldwide total number of subjects

311

EEA total number of subjects

113

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

261

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 338 subjects were screened and 311 subjects were randomised and treated with high dose (156 subjects), mid dose (77 subjects) and low dose (78 subjects). The safety evaluation set (SES) is the subset of all subjects treated with study medication at least once.

Period 1 title

Overall period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Data analyst, Carer, Assessor, Subject

Are arms mutually exclusive

Yes

High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Arm description

Subjects received 16 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 400 U per injection treatment via intramuscular injection into spastic muscles.

Arm type

Experimental

Investigational medicinal product name

Incobotulinumtoxin A

Investigational medicinal product code

NT 201

Other name

Xeomin; Botulinum toxin type A (150 kiloDalton) free from complexing proteins

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 16 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 400 U per injection treatment via intramuscular injection into spastic muscles.

Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Arm description

Subjects received 12 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 300 U per injection treatment via intramuscular injection into spastic muscles.

Arm type

Experimental

Investigational medicinal product name

Incobotulinumtoxin A

Investigational medicinal product code

NT 201

Other name

Xeomin; Botulinum toxin type A (150 kiloDalton) free from complexing proteins

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 12 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 300 U per injection treatment via intramuscular injection into spastic muscles.

Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Arm description

Subjects received 4 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 100 U per injection treatment via intramuscular injection into spastic muscles.

Arm type

Experimental

Investigational medicinal product name

Incobotulinumtoxin A

Investigational medicinal product code

NT 201

Other name

Xeomin; Botulinum toxin type A (150 kiloDalton) free from complexing proteins

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 4 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 100 U per injection treatment via intramuscular injection into spastic muscles.

Number of subjects in period 1	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Started	156	77	78
Completed	139	70	69
Not completed	17	7	9
Physician decision	1	1	2
Consent withdrawn by subject	7	4	3
Adverse event, non-fatal	1	-	-
Not specified	3	1	3
Lost to follow-up	2	-	1
Lack of efficacy	2	1	-
Protocol deviation	1	-	-

Baseline characteristics

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Reporting group title

High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Reporting group description

Subjects received 16 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 400 U per injection treatment via intramuscular injection into spastic muscles.

Reporting group title

Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Reporting group description

Subjects received 12 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 300 U per injection treatment via intramuscular injection into spastic muscles.

Reporting group title

Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Reporting group description

Subjects received 4 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 100 U per injection treatment via intramuscular injection into spastic muscles.

Reporting group values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Total
Number of subjects	156	77	78	311
Age categorical
Units: Subjects
Children (2-11 years)	131	67	63	261
Adolescents (12-17 years)	25	10	15	50
Age continuous
Units: years
arithmetic mean (standard deviation)	6.4 ( 3.9 )	6.6 ( 3.8 )	7.1 ( 4.6 )	-
Gender categorical
Units: Subjects
Female	83	44	42	169
Male	73	33	36	142

End points

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Reporting group title

High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Reporting group description

Subjects received 16 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 400 U per injection treatment via intramuscular injection into spastic muscles.

Reporting group title

Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Reporting group description

Subjects received 12 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 300 U per injection treatment via intramuscular injection into spastic muscles.

Reporting group title

Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Reporting group description

Subjects received 4 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 100 U per injection treatment via intramuscular injection into spastic muscles.

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

FAS population is subset in the Safety evaluation set (SES) for whom the primary efficacy variable (for all subjects who had at least an Ashworth Scale [AS] score of plantar flexor at baseline [Day 1 of the first injection cycle] or the investigator’s Global Impression of Change of Plantar Flexor Spasticity Scale (GICS-PF) [for subjects with bilateral treatment on same body side as chosen for the primary efficacy variable] at Day 29 [Week 4] of the first injection cycle) were available as part of end points reporting groups

Primary: 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)

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End point title

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)

End point description

The Ashworth Scale(AS) is a well known and commonly used scale in clinical trials with spasticity. In spastic muscles, 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). Subjects with bilateral pes equinus, body side for primary efficacy analysis i.e. “primary body side” was decided by investigator at screening and was kept throughout the entire study. Subjects with unilateral treatment, 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. The value 999 indicates that no data is available from the respective specific model.

End point type

Primary

End point timeframe

Baseline, Week 4

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[1]	77 ^[2]	78 ^[3]
Units: Units on a scale
least squares mean (standard error)
Week 4 of 1st IC (high versus low; n=156, 78)	-0.7 ( 0.061 )	999 ( 999 )	-0.66 ( 0.084 )
Week 4 of 1st IC (mid versus low; n=77, n=78)	999 ( 999 )	-0.7 ( 0.089 )	-0.66 ( 0.088 )

Notes
[1] - FAS
[2] - FAS
[3] - FAS

Statistical analysis 1

Comparison groups

Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin) v High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Number of subjects included in analysis

234

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.65

Method

Mixed Model Repeated Measure

Parameter type

LS-Mean difference

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.23

upper limit

0.14

Statistical analysis 2

Comparison groups

Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin) v Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.741

Method

Mixed Model Repeated Measure

Parameter type

LS-Mean difference

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

0.18

Primary: 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 (1st IC)

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End point title

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 (1st IC)

End point description

This variable is classified as co-primary to satisfy 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 subjects with bilateral pes equinus, 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 subjects with unilateral treatment, treated body side was kept throughout the entire study. 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. The value 999 indicates that no data is available from the respective specific model

End point type

Primary

End point timeframe

Baseline, Week 4

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[4]	77 ^[5]	78 ^[6]
Units: Units on a scale
least squares mean (standard error)
Week 4 of 1st IC (high versus low; n=156, 78)	1.53 ( 0.059 )	999 ( 999 )	1.37 ( 0.081 )
Week 4 of 1st IC (mid versus low; n=77, n=78)	999 ( 999 )	1.38 ( 0.092 )	1.32 ( 0.09 )

Notes
[4] - FAS
[5] - FAS
[6] - FAS

Statistical analysis 1

Comparison groups

High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin) v Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Number of subjects included in analysis

234

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.075

Method

Mixed Model Repeated Measure

Parameter type

LS-Mean difference

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.34

Statistical analysis 2

Comparison groups

Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin) v Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.603

Method

Mixed Model Repeated Measure

Parameter type

LS-Mean difference

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

0.27

Secondary: Change From Baseline in the AS Score of Plantar Flexors of the Nonprimary Body Side in Subjects With Bilateral Treatment at Day 29 (Week 4) of the First (1st) and Second Injection Cycle (2nd IC)

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End point title

Change From Baseline in the AS Score of Plantar Flexors of the Nonprimary Body Side in Subjects With Bilateral Treatment at Day 29 (Week 4) of the First (1st) and Second Injection Cycle (2nd IC)

End point description

The 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 and are therefore provided separately for each comparison. The value 999 indicates that no data is available from the respective specific model.

End point type

Secondary

End point timeframe

Baseline, Week 4 of 1st IC and Week 16-40 of 2nd IC

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[7]	77 ^[8]	78 ^[9]
Units: Units on a scale
least squares mean (standard error)
Week 4 of 1st IC (high versus low; n=114, 54)	-0.76 ( 0.073 )	999 ( 999 )	-0.61 ( 0.104 )
Week 4 of 1st IC (mid versus low; n=58, 54)	999 ( 999 )	-0.6 ( 0.105 )	-0.58 ( 0.108 )
Week 4 of 2nd IC (high versus low; n=104, 53)	-0.95 ( 0.077 )	999 ( 999 )	-0.74 ( 0.106 )
Week 4 of 2nd IC (mid versus low; n=53, 53)	999 ( 999 )	-0.85 ( 0.124 )	-0.76 ( 0.123 )

Notes
[7] - FAS
[8] - FAS
[9] - FAS

No statistical analyses for this end point

Secondary: 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

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End point title

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

End point description

The 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 subjects 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 subjects with unilateral treatment, the treated body side was kept throughout the entire study. Values represent LS mean differences between baseline and the respective week (w) 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. The value 999 indicates that no data is available from the respective specific model.

End point type

Secondary

End point timeframe

Baseline to Week 4 of 2nd IC (Week 16-40)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[10]	77 ^[11]	78 ^[12]
Units: Units on a scale
least squares mean (standard error)
Week 4 of 2nd IC (high versus low; n=143, 73)	-0.89 ( 0.061 )	999 ( 999 )	-0.82 ( 0.082 )
Week 4 of 2nd IC (mid versus low; n=71, n=73)	999 ( 999 )	-1.03 ( 0.094 )	-0.85 ( 0.091 )

Notes
[10] - FAS
[11] - FAS
[12] - FAS

No statistical analyses for this end point

Secondary: 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 1st and of the 2nd Injection Cycle (IC)

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End point title

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 1st and of the 2nd Injection Cycle (IC)

End point description

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). Subjects 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. Subjects with unilateral treatment, the treated body side was kept throughout the entire study. Values represent LS mean differences between baseline and the respective week (w) 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. The value 999 indicates that no data is available from the respective specific model.

End point type

Secondary

End point timeframe

Baseline to week 8 and 12 of 1st IC and 2nd IC (week 20-44 and 24-48)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156	77	78
Units: Units on a scale
least squares mean (standard error)
Week 8 of 1st IC (high versus low; n=156, 78)	-0.62 ( 0.059 )	999 ( 999 )	-0.69 ( 0.08 )
Week 8 of 1st IC (mid versus low; n=77, n=78)	999 ( 999 )	-0.74 ( 0.088 )	-0.69 ( 0.086 )
Week 12 of 1st IC (high versus low; n=156, 78)	-0.43 ( 0.056 )	999 ( 999 )	-0.58 ( 0.077 )
Week 12 of 1st IC (mid versus low; n=77, n=78)	999 ( 999 )	-0.45 ( 0.086 )	-0.59 ( 0.085 )
Week 8 of 2nd IC (high versus low; n=143, 73)	-0.76 ( 0.058 )	999 ( 999 )	-0.76 ( 0.079 )
Week 8 of 2nd IC (mid versus low; n=71, 73)	999 ( 999 )	-0.92 ( 0.092 )	-0.79 ( 0.09 )
Week 12 of 2nd IC (high versus low; n=143, 73)	-0.57 ( 0.058 )	999 ( 999 )	-0.65 ( 0.079 )
Week 12 of 2nd IC (mid versus low; n=71, 73)	999 ( 999 )	-0.64 ( 0.088 )	-0.68 ( 0.085 )

No statistical analyses for this end point

Secondary: Changes From Baseline in AS Score of Knee Flexors or Thigh Adductors in Subjects With Unilateral Treatment at Day 29 (Week 4) of the First and Second Injection Cycle (IC)

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End point title

Changes From Baseline in AS Score of Knee Flexors or Thigh Adductors in Subjects With Unilateral Treatment at Day 29 (Week 4) of the First and Second Injection Cycle (IC)

End point description

The 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 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. The value 999 indicates that no data is available from the respective specific model.

End point type

Secondary

End point timeframe

Baseline to Week 4 of 1st IC and 2nd IC (Week 16-40)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[13]	77 ^[14]	78 ^[15]
Units: Units on a scale
least squares mean (standard error)
KF, w 4 of 1st IC (high versus low; n=30, 19)	-0.6 ( 0.18 )	999 ( 999 )	-0.39 ( 0.214 )
KF, w 4 of 1st IC (mid versus low; n=11, 19)	999 ( 999 )	-0.07 ( 0.285 )	-0.32 ( 0.204 )
KF, w 4 of 2nd IC (high versus low; n=27, 16)	-0.64 ( 0.173 )	999 ( 999 )	-0.79 ( 0.2 )
KF, w 4 of 2nd IC (mid versus low; n=10, 16)	999 ( 999 )	-0.31 ( 0.269 )	-0.67 ( 0.19 )
TA, w 4 of 1st IC (high versus low; n=12, 5)	-0.61 ( 0.287 )	999 ( 999 )	-0.76 ( 0.506 )
TA, w 4 of 1st IC (mid versus low; n=8, 5)	999 ( 999 )	999 ( 999 )	999 ( 999 )
TA, w 4 of 2nd IC (high versus low; n=11, 4)	999 ( 999 )	999 ( 999 )	999 ( 999 )
TA, w 4 of 2nd IC (mid versus low; n=8, 4)	999 ( 999 )	999 ( 999 )	999 ( 999 )

Notes
[13] - FAS
[14] - FAS
[15] - FAS

No statistical analyses for this end point

Secondary: 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 (IC)

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End point title

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 (IC)

End point description

The 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 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. The value 999 indicates that no data is available respective specific model.

End point type

Secondary

End point timeframe

Baseline to Week 4, 8, and 12 of 1st IC and 2nd IC (Week 16-40, 20-44 and 24-48)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[16]	77 ^[17]	78 ^[18]
Units: Units on a scale
least squares mean (standard error)
Week 4 of 1st IC (high versus low; n=156, 78)	-2.38 ( 0.897 )	999 ( 999 )	-2.56 ( 1.231 )
Week 4 of 1st IC (mid versus low; n=77, 78)	999 ( 999 )	-0.88 ( 1.389 )	-2.47 ( 1.367 )
Week 8 of 1st IC (high versus low; n=156, 78)	-3.15 ( 0.921 )	999 ( 999 )	-2.63 ( 1.267 )
Week 8 of 1st IC (mid versus low; n=77, 78)	999 ( 999 )	-1.74 ( 1.393 )	-2.56 ( 1.372 )
Week 12 of 1st IC (high versus low; n=156, 78)	-3.1 ( 0.848 )	999 ( 999 )	-2.67 ( 1.157 )
Week 12 of 1st IC (mid versus low; n=77, 78)	999 ( 999 )	-0.07 ( 1.231 )	-2.59 ( 1.213 )
Week 4 of 2nd IC (high versus low; n=143, 73)	-4.72 ( 1.173 )	999 ( 999 )	-3.83 ( 1.594 )
Week 4 of 2nd IC (mid versus low; n=71, 73)	999 ( 999 )	-3.24 ( 1.773 )	-3.6 ( 1.713 )
Week 8 of 2nd IC (high versus low; n=143, 73)	-4.72 ( 1.065 )	999 ( 999 )	-4.25 ( 1.44 )
Week 8 of 2nd IC (mid versus low; n=71, 73)	999 ( 999 )	-2.97 ( 1.634 )	-4.04 ( 1.575 )
Week 12 of 2nd IC (high versus low; n=143, 73)	-4.27 ( 0.968 )	999 ( 999 )	-5.68 ( 1.298 )
Week 12 of 2nd IC (mid versus low; n=71, 73)	999 ( 999 )	-2.12 ( 1.519 )	-5.45 ( 1.455 )

Notes
[16] - FAS
[17] - FAS
[18] - FAS

No statistical analyses for this end point

Secondary: Investigator's, Child's/Adolescent's, and Parent's/Caregiver's Global Impression of Change Scale [GICS] at Day 29 (week 4) of the 1st and 2nd Injection Cycle

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End point title

Investigator's, Child's/Adolescent's, and Parent's/Caregiver's Global Impression of Change Scale [GICS] at Day 29 (week 4) of the 1st and 2nd Injection Cycle

End point description

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 LS mean differences between baseline and the respective week (w) 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. Inv = Investigator; S = Subject; P/C = Parent/Caregiver. The value 999 indicates that no data is available from the respective specific model.

End point type

Secondary

End point timeframe

Baseline to Week 4 of 1st IC and 2nd IC (Week 16-40)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[19]	77 ^[20]	78 ^[21]
Units: Units on a scale
least squares mean (standard error)
Inv, 1st IC (high versus low; n=156, 78)	1.5 ( 0.056 )	999 ( 999 )	1.35 ( 0.076 )
Inv, 1st IC (mid versus low; n=77, 78)	999 ( 999 )	1.36 ( 0.087 )	1.33 ( 0.086 )
S, 1st IC (high versus low; n=67, 41)	1.72 ( 0.205 )	999 ( 999 )	1.64 ( 0.223 )
S, 1st IC (mid versus low; n=42, 41)	999 ( 999 )	1.17 ( 0.203 )	1.3 ( 0.216 )
P/C, 1st IC (high versus low; n=156, 78)	1.53 ( 0.068 )	999 ( 999 )	1.43 ( 0.092 )
P/C, 1st IC (mid versus low; n=77, 78)	999 ( 999 )	1.26 ( 0.107 )	1.39 ( 0.105 )
Inv, 2nd IC (high versus low; n=143, 73)	1.46 ( 0.071 )	999 ( 999 )	1.38 ( 0.096 )
Inv, 2nd IC (mid versus low; n=77, 73)	999 ( 999 )	1.56 ( 0.11 )	1.46 ( 0.104 )
S, 2nd IC (high versus low; n=60, 36)	1.53 ( 0.21 )	999 ( 999 )	1.66 ( 0.224 )
S, 2nd IC (mid versus low; n=39, 36)	999 ( 999 )	1.44 ( 0.276 )	1.53 ( 0.283 )
P/C, 2nd IC (high versus low; n=143, 73)	1.45 ( 0.076 )	999 ( 999 )	1.34 ( 0.101 )
P/C, 2nd IC (mid versus low; n=71, 73)	999 ( 999 )	1.67 ( 0.115 )	1.4 ( 0.109 )

Notes
[19] - FAS
[20] - FAS
[21] - FAS

No statistical analyses for this end point

Secondary: 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

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End point title

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

End point description

The GICS are global outcomes to assess the impression of change due to treatment. GICS were assessed by the investigator, by the subject(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). Subjects with bilateral pes equinus, body side for primary efficacy analysis i.e. “primary body side” was decided by investigator at screening and was kept throughout the entire study. Subjects with unilateral treatment, treated body side was kept throughout the entire study. Values represent 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.The value 999 indicates that no data is available from the respective specific model.

End point type

Secondary

End point timeframe

Baseline to Week 4 of 1st IC and 2nd IC (Week 16-40)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[22]	77 ^[23]	78 ^[24]
Units: Units on a scale
least squares mean (standard error)
Week 4 of 1st IC (high versus low; n=156, 78)	1.53 ( 0.059 )	999 ( 999 )	1.37 ( 0.081 )
Week 4 of 1st IC (mid versus low; n=77, 78)	999 ( 999 )	1.38 ( 0.092 )	1.32 ( 0.09 )
Week 4 of 2nd IC (high versus low; n=143, 73)	1.43 ( 0.073 )	999 ( 999 )	1.38 ( 0.098 )
Week 4 of 2nd IC (mid versus low; n=71, 73)	999 ( 999 )	1.54 ( 0.11 )	1.48 ( 0.103 )

Notes
[22] - FAS
[23] - FAS
[24] - FAS

No statistical analyses for this end point

Secondary: 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

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End point title

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

End point description

The GMFM-66 is a standardized observational 66-item instrument designed and validated to measure change in gross motor function over time in subjects with cerebral palsy. Score values represent the total GMFM-66 score. Total GMFM scores range from 0 (worst) to 100 (best). Values represent 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. The value 999 indicates that no data is available from the respective specific model.

End point type

Secondary

End point timeframe

Baseline to Week 12-36 of 1st IC and 2nd IC (End of study = Week 24-72)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[25]	77 ^[26]	78 ^[27]
Units: Units on a scale
least squares mean (standard error)
W 12-36 of 1st IC (high versus low; n=155, 77)	1.23 ( 0.288 )	999 ( 999 )	1.64 ( 0.392 )
W 12-36 of 1st IC (mid versus low; n=77, 77)	999 ( 999 )	1.14 ( 0.448 )	1.49 ( 0.445 )
W 12-36 of 2nd IC (high versus low; n=155, 77)	2.31 ( 0.359 )	999 ( 999 )	2.46 ( 0.488 )
W 12-36 of 2nd IC (mid versus low; n=77, 77)	999 ( 999 )	3.1 ( 0.542 )	2.59 ( 0.539 )

Notes
[25] - FAS
[26] - FAS
[27] - FAS

No statistical analyses for this end point

Secondary: Change in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) to all Post Baseline Visits of the 1st and of the 2nd Injection Cycle

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End point title

Change in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) to all Post Baseline Visits of the 1st and of the 2nd Injection Cycle

End point description

The QPS is a patient-reported outcome for children and adolescents (2-17 years) with cerebral palsy on spasticity-related pain. Pain intensity (from subjects) 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 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. S = Subject; P/C = Parent/Caregiver; w = week. The value 999 indicates that no data is available from the respective specific model.

End point type

Secondary

End point timeframe

Baseline to Week 4, 8, and 12 of 1st IC and 2nd IC (Week 16-40, 20-44 and 24-48)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[28]	77 ^[29]	78 ^[30]
Units: Units on a scale
least squares mean (standard error)
S, w 4 of 1st IC (high versus low; n=72, 42)	-0.66 ( 0.198 )	999 ( 999 )	-1.32 ( 0.23 )
S, w 4 of 1st IC (mid versus low; n=42, 42)	999 ( 999 )	-1.02 ( 0.301 )	-1.61 ( 0.31 )
S, w 8 of 1st IC (high versus low; n=72, 42)	-0.6 ( 0.228 )	999 ( 999 )	-0.93 ( 0.265 )
S, w 8 of 1st IC (mid versus low; n=42, 42)	999 ( 999 )	-0.94 ( 0.299 )	-1.06 ( 0.308 )
S, w 12 of 1st IC (high versus low; n=72, 42)	-0.42 ( 0.207 )	999 ( 999 )	-1.13 ( 0.241 )
S, w 12 of 1st IC (mid versus low; n=42, 42)	999 ( 999 )	-1.14 ( 0.253 )	-1.47 ( 0.261 )
P/C, w 4 of 1st IC (high versus low; n=64, 39)	-0.44 ( 0.067 )	999 ( 999 )	-0.49 ( 0.089 )
P/C, w 4 of 1st IC (mid versus low; n=39, 39)	999 ( 999 )	-0.31 ( 0.094 )	-0.34 ( 0.093 )
P/C, w 8 of 1st IC (high versus low; n=64, 39)	-0.48 ( 0.069 )	999 ( 999 )	-0.47 ( 0.092 )
P/C, w 8 of 1st IC (mid versus low; n=39, 39)	999 ( 999 )	-0.29 ( 0.092 )	-0.33 ( 0.091 )
P/C, w 12, 1st IC (high versus low; n=64, 39)	-0.44 ( 0.071 )	999 ( 999 )	-0.37 ( 0.095 )
P/C, w 12, 1st IC (mid versus low; n=39, 39)	999 ( 999 )	-0.21 ( 0.095 )	-0.3 ( 0.095 )
S, w 4 of 2nd IC (high versus low; n=72, 42)	-0.53 ( 0.26 )	999 ( 999 )	-1.03 ( 0.289 )
S, w 4 of 2nd IC (mid versus low; n=42, 42)	999 ( 999 )	-1.36 ( 0.347 )	-1.53 ( 0.351 )
S, w 8 of 2nd IC (high versus low; n=72, 42)	-0.78 ( 0.272 )	999 ( 999 )	-1.16 ( 0.302 )
S, w 8 of 2nd IC (mid versus low; n=42, 42)	999 ( 999 )	-1.56 ( 0.312 )	-1.61 ( 0.315 )
S, w 12 of 2nd IC (high versus low; n=72, 42)	-0.34 ( 0.299 )	999 ( 999 )	-0.97 ( 0.333 )
S, w 12 of 2nd IC (mid versus low; n=72, 42)	999 ( 999 )	-1.37 ( 0.333 )	-1.4 ( 0.336 )
P/C, w 4 of 2nd IC (high versus low; n=64, 39)	-0.54 ( 0.078 )	999 ( 999 )	-0.47 ( 0.102 )
P/C, w 4 of 2nd IC (mid versus low; n=39, 39)	999 ( 999 )	-0.59 ( 0.111 )	-0.46 ( 0.105 )
P/C, w 8 of 2nd IC (high versus low; n=64, 39)	-0.55 ( 0.08 )	999 ( 999 )	-0.47 ( 0.104 )
P/C, w 8 of 2nd IC (mid versus low; n=39, 39)	999 ( 999 )	-0.54 ( 0.119 )	-0.44 ( 0.113 )
P/C, w 12, 2nd IC (high versus low; n=64, 39)	-0.49 ( 0.085 )	999 ( 999 )	-0.4 ( 0.112 )
P/C, w 12, 2nd IC (mid versus low; n=39, 39)	999 ( 999 )	-0.52 ( 0.128 )	-0.33 ( 0.121 )

Notes
[28] - FAS
[29] - FAS
[30] - FAS

No statistical analyses for this end point

Secondary: Time to Reinjection for Each of the Three Dose Groups for the 1st and 2nd Injection Cycle

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End point title

Time to Reinjection for Each of the Three Dose Groups for the 1st and 2nd Injection Cycle

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 24-72

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[31]	77 ^[32]	78 ^[33]
Units: Weeks
arithmetic mean (standard deviation)
1st Injection cycle (n=143, 77, 73)	15.3 ( 4.6 )	15.9 ( 5.7 )	15.7 ( 5.9 )
2nd Injection Cycle (n= 110, 51, 57)	17 ( 6.5 )	17.9 ( 7.8 )	15.5 ( 4.9 )

Notes
[31] - FAS
[32] - FAS
[33] - FAS

No statistical analyses for this end point

Secondary: Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Injection Cycle

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End point title

Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Injection Cycle

End point description

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 subjects affected.

End point type

Secondary

End point timeframe

Up to End of study visit (Week 24-72)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[34]	77 ^[35]	78 ^[36]
Units: Subjects
1st Injection Cycle	53	15	18
2nd Injection Cycle	44	15	21
Overall Period	77	26	30

Notes
[34] - FAS
[35] - FAS
[36] - FAS

No statistical analyses for this end point

Secondary: Occurrence of Subjects with TEAEs of Special Interest (TEAESIs) Overall and per Injection Cycle

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End point title

Occurrence of Subjects with TEAEs of Special Interest (TEAESIs) Overall and per Injection Cycle

End point description

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 subjects affected.

End point type

Secondary

End point timeframe

Up to end of study visit (Week 24-72)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[37]	77 ^[38]	78 ^[39]
Units: Subjects
1st Injection Cycle	4	1	0
2nd Injection Cycle	2	0	1
Overall Period	5	1	1

Notes
[37] - FAS
[38] - FAS
[39] - FAS

No statistical analyses for this end point

Secondary: Occurrence of Serious TEAEs (TESAEs) Overall and per Injection Cycle

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End point title

Occurrence of Serious TEAEs (TESAEs) Overall and per Injection Cycle

End point description

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 subjects affected.

End point type

Secondary

End point timeframe

Up to end of study visit (Week 24-72)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[40]	77 ^[41]	78 ^[42]
Units: Subjects
1st Injection Cycle	4	0	3
2nd Injection Cycle	3	1	3
Overall Period	7	1	6

Notes
[40] - FAS
[41] - FAS
[42] - FAS

No statistical analyses for this end point

Secondary: Occurrence of TEAEs Related to Treatment as Assessed by the Investigator Overall and per Injection Cycle

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End point title

Occurrence of TEAEs Related to Treatment as Assessed by the Investigator Overall and per Injection Cycle

End point description

End point type

Secondary

End point timeframe

Up to end of study visit (Week 24-72)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[43]	77 ^[44]	78 ^[45]
Units: Subjects
1st Injection Cycle	7	1	2
2 nd Injection Cycle	4	1	1
Overall Period	11	2	2

Notes
[43] - FAS
[44] - FAS
[45] - FAS

No statistical analyses for this end point

Secondary: Occurrence of TEAEs by Worst Intensity Overall and per Injection Cycle

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End point title

Occurrence of TEAEs by Worst Intensity Overall and per Injection Cycle

End point description

End point type

Secondary

End point timeframe

Up to end of study visit (Week 24-72)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[46]	77 ^[47]	78 ^[48]
Units: Subjects
1st Injection Cycle: Mild AE’s	35	6	14
1st Injection Cycle: Moderate AE’s	17	9	4
1st Injection Cycle: Severe AE’s	1	0	0
2nd Injection Cycle: Mild AE’s	24	9	11
2nd Injection Cycle: Moderate AE’s	18	5	9
2nd Injection Cycle: Severe AE’s	2	1	1
Overall: Mild AE’s	41	14	19
Overall: Moderate AE’s	33	11	10
Overall: Severe AE’s	3	1	1

Notes
[46] - FAS
[47] - FAS
[48] - FAS

No statistical analyses for this end point

Secondary: Occurrence of TEAEs by Final Outcome Overall and per Injection Cycle

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End point title

Occurrence of TEAEs by Final Outcome Overall and per Injection Cycle

End point description

End point type

Secondary

End point timeframe

Up to end of study visit (Week 24-72)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[49]	77 ^[50]	78 ^[51]
Units: Subjects
1st Injection Cycle: recovered/resolved	52	15	17
1st Injection Cycle: recovering/resolving	0	0	0
1st Injection Cycle: not recovered/ not resolved	3	0	1
1st Injection Cycle: recovered/resolved w/ sequela	1	0	0
1st Injection Cycle: fatal	0	0	0
1st Injection Cycle: unknown	1	0	0
2nd Injection Cycle: recovered/resolved	42	14	20
2nd Injection Cycle: recovering/resolving	2	1	0
2nd Injection Cycle: not recovered/ not resolved	3	2	2
2nd Injection Cycle: recovered/resolved w/ sequela	0	0	0
2nd Injection Cycle: fatal	0	0	0
2nd Injection Cycle: unknown	0	0	0
Overall: recovered/resolved	74	25	28
Overall: recovering/resolving	2	1	0
Overall: not recovered/ not resolved	6	2	3
Overall: recovered/resolved w/ sequelae	1	0	0
Overall: fatal	0	0	0
Overall: unknown	1	0	0

Notes
[49] - FAS
[50] - FAS
[51] - FAS

No statistical analyses for this end point

Secondary: Occurrence of TEAEs leading to Discontinuation Overall and per Injection Cycle

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End point title

Occurrence of TEAEs leading to Discontinuation Overall and per Injection Cycle

End point description

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 subjects affected.

End point type

Secondary

End point timeframe

Up to end of study visit (Week 24-72)

End point values	High Dose: 16 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg Body Weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
Number of subjects analysed	156 ^[52]	77 ^[53]	78 ^[54]
Units: Subjects
1st Injection Cycle	1	0	0
2nd Injection Cycle	0	0	0
Overall Period	1	0	0

Notes
[52] - FAS
[53] - FAS
[54] - FAS

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the timepoint of first injection until end of study visit (week 24-72)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin)

Reporting group description

Subjects received 16 U/kg BW of IncobotulinumtoxinA (Xeomin) with a maximum of 400 U per injection treatment via intramuscular injection into spastic muscles.

Reporting group title

Low Dose: 4 U/kg body weight IncobotulinumtoxinA (Xeomin)

Reporting group description

Subjects received 4 U/kg body weight of IncobotulinumtoxinA (Xeomin) with a maximum of 100 U per injection treatment via intramuscular injection into spastic muscles.

Reporting group title

Mid Dose: 12 U/kg body weight IncobotulinumtoxinA (Xeomin)

Reporting group description

Subjects received 12 U/kg body weight of IncobotulinumtoxinA (Xeomin) with a maximum of 300 U per injection treatment via intramuscular injection into spastic muscles.

Serious adverse events	High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg body weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg body weight IncobotulinumtoxinA (Xeomin)
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 156 (4.49%)	6 / 78 (7.69%)	1 / 77 (1.30%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Injury, poisoning and procedural complications
Brain contusion
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 156 (0.00%)	1 / 78 (1.28%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Concussion
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Craniocerebral injury
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Humerus fracture
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 156 (0.00%)	1 / 78 (1.28%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laceration
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 156 (0.00%)	1 / 78 (1.28%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Strabismus correction
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 156 (0.00%)	1 / 78 (1.28%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Epilepsy
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile convulsion
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 156 (0.00%)	1 / 78 (1.28%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	0 / 156 (0.00%)	1 / 78 (1.28%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Nausea
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 156 (0.00%)	1 / 78 (1.28%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthritis reactive
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bursitis
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Synovitis
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	1 / 78 (1.28%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Borrelia infection
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal infection
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 156 (0.00%)	1 / 78 (1.28%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tonsillitis
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 156 (0.64%)	0 / 78 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 156 (0.00%)	0 / 78 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	High Dose: 16 U/kg body weight IncobotulinumtoxinA (Xeomin)	Low Dose: 4 U/kg body weight IncobotulinumtoxinA (Xeomin)	Mid Dose: 12 U/kg body weight IncobotulinumtoxinA (Xeomin)
Total subjects affected by non serious adverse events
subjects affected / exposed	23 / 156 (14.74%)	15 / 78 (19.23%)	10 / 77 (12.99%)
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 156 (1.92%)	4 / 78 (5.13%)	1 / 77 (1.30%)
occurrences all number	5	5	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	17 / 156 (10.90%)	9 / 78 (11.54%)	8 / 77 (10.39%)
occurrences all number	32	11	15
Bronchitis
subjects affected / exposed	3 / 156 (1.92%)	7 / 78 (8.97%)	1 / 77 (1.30%)
occurrences all number	6	7	1

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Were there any global substantial amendments to the protocol? Yes

15 Jul 2013

This amendment includes clarification that occurrence of severe Adverse event of special interest (AESI) of respiratory function or severe swallowing disorders were criteria for premature study discontinuation of subjects without any further re-exposure to Investigational product (IP). Addition of swallowing disorders to respiratory disorders as AESI category that could lead to premature discontinuation of the study. Clarification that an End of Study Visit was to be conducted whenever possible at any time point, if a subject discontinued study participation, not only after the first injection cycle. Clarification that hospitalization for analgosedation starting one day before or on the day of injection treatments was not regarded as an Serious adverse event (SAE), if performed for organizational reasons only. Addition of estimated Glomerular filtration rate (GFR) to assess subject’s renal function based on the height and creatinine levels. Clarification of regulation to keep clinical patterns of spasticity treatment throughout participation in this trial and to keep these patterns also in subjects rolling over to the open-label study. Clarification of the calculation of the visit window in case of visits where the Gross Motor Function Measure (GMFM) was performed one day prior to all other assessments. Correction of ranges for injection sites for the gastrocnemius muscle and for all other muscles in the Gross Motor Function Measure (CSP) to be in line with the regulation of maximum of 25 units (U) per injection site in subjects less than (<) 25 kilogram (kg) body weight (BW) and maximum of 50 U in subjects with BW greater than or equal to (≥) 25 kg. Description how confidential data were handled on the GMFM-66 source form. Change in order of appearance of assessments in overview of study activities were aligned with descriptions in separate outcome manual for the study.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 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)

Primary: 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)

Primary: 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 (1st IC)

Primary: 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 (1st IC)

Secondary: Change From Baseline in the AS Score of Plantar Flexors of the Nonprimary Body Side in Subjects With Bilateral Treatment at Day 29 (Week 4) of the First (1st) and Second Injection Cycle (2nd IC)

Secondary: Change From Baseline in the AS Score of Plantar Flexors of the Nonprimary Body Side in Subjects With Bilateral Treatment at Day 29 (Week 4) of the First (1st) and Second Injection Cycle (2nd IC)

Secondary: 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

Secondary: 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

Secondary: 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 1st and of the 2nd Injection Cycle (IC)

Secondary: 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 1st and of the 2nd Injection Cycle (IC)

Secondary: Changes From Baseline in AS Score of Knee Flexors or Thigh Adductors in Subjects With Unilateral Treatment at Day 29 (Week 4) of the First and Second Injection Cycle (IC)

Secondary: Changes From Baseline in AS Score of Knee Flexors or Thigh Adductors in Subjects With Unilateral Treatment at Day 29 (Week 4) of the First and Second Injection Cycle (IC)

Secondary: 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 (IC)

Secondary: 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 (IC)

Secondary: Investigator's, Child's/Adolescent's, and Parent's/Caregiver's Global Impression of Change Scale [GICS] at Day 29 (week 4) of the 1st and 2nd Injection Cycle

Secondary: Investigator's, Child's/Adolescent's, and Parent's/Caregiver's Global Impression of Change Scale [GICS] at Day 29 (week 4) of the 1st and 2nd Injection Cycle

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: Change in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) to all Post Baseline Visits of the 1st and of the 2nd Injection Cycle

Secondary: Change in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) to all Post Baseline Visits of the 1st and of the 2nd Injection Cycle

Secondary: Time to Reinjection for Each of the Three Dose Groups for the 1st and 2nd Injection Cycle

Secondary: Time to Reinjection for Each of the Three Dose Groups for the 1st and 2nd Injection Cycle

Secondary: Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Injection Cycle

Secondary: Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Injection Cycle

Secondary: Occurrence of Subjects with TEAEs of Special Interest (TEAESIs) Overall and per Injection Cycle

Secondary: Occurrence of Subjects with TEAEs of Special Interest (TEAESIs) Overall and per Injection Cycle

Secondary: Occurrence of Serious TEAEs (TESAEs) Overall and per Injection Cycle

Secondary: Occurrence of Serious TEAEs (TESAEs) Overall and per Injection Cycle

Secondary: Occurrence of TEAEs Related to Treatment as Assessed by the Investigator Overall and per Injection Cycle

Secondary: Occurrence of TEAEs Related to Treatment as Assessed by the Investigator Overall and per Injection Cycle

Secondary: Occurrence of TEAEs by Worst Intensity Overall and per Injection Cycle

Secondary: Occurrence of TEAEs by Worst Intensity Overall and per Injection Cycle

Secondary: Occurrence of TEAEs by Final Outcome Overall and per Injection Cycle

Secondary: Occurrence of TEAEs by Final Outcome Overall and per Injection Cycle

Secondary: Occurrence of TEAEs leading to Discontinuation Overall and per Injection Cycle

Secondary: Occurrence of TEAEs leading to Discontinuation Overall and per Injection Cycle

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
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