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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 upper limb spasticity alone or combined upper and lower limb spasticity in children and adolescents (age 2 - 17 years) with cerebral palsy.

Summary
EudraCT number	2012-005496-14
Trial protocol	PL Outside EU/EEA
Global end of trial date	28 Aug 2018

Results information
Results version number	v2(current)
This version publication date	18 Aug 2019
First version publication date	10 Mar 2019
Other versions	v1
Version creation reason	Correction of full data set Zero AEs observed replaced with zero participants analyzed for various data points in several AE-related endpoints

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_3072_1

ISRCTN number

US NCT number

NCT02002884

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 6915031, clinicaltrials@merz.de

Scientific contact

Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 6915031, clinicaltrials@merz.de

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

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?

Yes

Analysis stage

Final

Date of interim/final analysis

12 Dec 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Aug 2018

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of one or both upper limbs (UL) alone or in combination with injections into one or both lower limbs (LL) are effective and safe in treating children/adolescents (age 2-17 years) with spasticity due to cerebral palsy.

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

28 Mar 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Mexico: 62

Country: Number of subjects enrolled

Argentina: 21

Country: Number of subjects enrolled

Russian Federation: 36

Country: Number of subjects enrolled

Ukraine: 122

Country: Number of subjects enrolled

United States: 27

Country: Number of subjects enrolled

Poland: 83

Worldwide total number of subjects

351

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

271

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

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

Screening details

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

Period 1 title

Main Period (MP)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Carer, Subject

Are arms mutually exclusive

Yes

MP Low Dose Group

Arm description

In MP, subjects randomized to low dose group were injected with doses of NT 201 ranging from 2 to 5 Units per kilogram (U/kg) body weight (BW) up to a total body dose of 125 Units (U).

Arm type

Experimental

Investigational medicinal product name

IncobotulinumtoxinA

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

On Day 1 of MP, subjects randomized to low dose group received intramuscular injections of 2 U/kg NT 201 (maximum of 50 U in subjects with more than [>] 25 kilogram [kg] BW) into spastic muscles of one of the UL. Treatment with fixed doses of either flexed elbow or flexed wrist or both was mandatory. If the contralateral UL or one or both LL were also treated, subjects received additional doses of NT 201. The total body dose ranged from 2 U/kg (50 U for subjects with >25kg BW) to 5 U/kg (125 U for subjects with >25kg BW) depending on the combination of treated limbs and the subject's Gross Motor Function Classification System (GMFCS) level.

MP Mid Dose Group

Arm description

In MP, subjects randomized to mid dose group were injected with doses of NT 201 ranging from 6 to 15 U/kg BW up to a total body dose of 375 U.

Arm type

Experimental

Investigational medicinal product name

IncobotulinumtoxinA

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

On Day 1 of MP, subjects randomized to mid dose group received intramuscular injections of 6 U/kg NT 201 (maximum of 150 U in subjects with >25kg BW) into spastic muscles of one of the UL. Treatment with fixed doses of either flexed elbow or flexed wrist or both was mandatory. If the contralateral UL or one or both LL were also treated, subjects received additional doses of NT 201. The total body dose ranged from 6 U/kg (150 U for subjects with >25kg BW) to 15 U/kg (375 U for subjects with >25kg BW) depending on the combination of treated limbs and the subject's GMFCS level.

MP High Dose Group

Arm description

In MP, subjects randomized to high dose group were injected with doses of NT 201 ranging from 8 to 20 U/kg BW up to a total body dose of 500 U.

Arm type

Experimental

Investigational medicinal product name

IncobotulinumtoxinA

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

On Day 1 of MP, subjects randomized to high dose group received intramuscular injections of 8 U/kg NT 201 (maximum of 200 U in subjects with >25kg BW) into spastic muscles of one of the UL. Treatment with fixed doses of either flexed elbow or flexed wrist or both was mandatory. If the contralateral UL or one or both LL were also treated, subjects received additional doses of NT 201. The total body dose ranged from 8 U/kg (200 U for subjects with >25kg BW) to 20 U/kg (500 U for subjects with >25kg BW) depending on the combination of treated limbs and the subject's GMFCS level.

Number of subjects in period 1	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group
Started	87	88	176
Treated	87	87	176
Completed	81	82	168
Not completed	6	6	8
Other	-	3	3
Adverse event, non-fatal	-	1	1
Consent withdrawn by subject	6	2	2
Lost to follow-up	-	-	2

Period 2 title

Open-Label Extension Period (OLEX)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

OLEX (3 Injections)

Arm description

Subjects who completed MP and qualified for further participation in the study were treated with doses of NT 201 between 8 and 20 U/kg (maximum body dose of 500 U in subjects with >25kg BW) in each of the three injection cycles in OLEX.

Arm type

Experimental

Investigational medicinal product name

IncobotulinumtoxinA

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

On Day 1 of each of the three injection cycles of OLEX, subjects who qualified for further participation in the study received intramuscular injections of 8 U/kg NT 201 (maximum of 200 U in subjects with >25kg BW) into spastic muscles of the UL selected for treatment in MP. Treatment with fixed doses of either flexed elbow or flexed wrist or both was mandatory. If the contralateral UL or one or both LL were also treated, subjects received additional doses of NT 201. The total body dose ranged from 8 U/kg (200 U for subjects with >25kg BW) to 20 U/kg (500 U for subjects with >25kg BW) depending on the combination of treated limbs and the subject's GMFCS level.

Number of subjects in period 2	OLEX (3 Injections)
Started	331
Completed	281
Not completed	50
Other	24
Physician decision	1
Adverse event, non-fatal	5
Consent withdrawn by subject	10
Lost to follow-up	10

Baseline characteristics

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Reporting group title

MP Low Dose Group

Reporting group description

In MP, subjects randomized to low dose group were injected with doses of NT 201 ranging from 2 to 5 Units per kilogram (U/kg) body weight (BW) up to a total body dose of 125 Units (U).

Reporting group title

MP Mid Dose Group

Reporting group description

In MP, subjects randomized to mid dose group were injected with doses of NT 201 ranging from 6 to 15 U/kg BW up to a total body dose of 375 U.

Reporting group title

MP High Dose Group

Reporting group description

In MP, subjects randomized to high dose group were injected with doses of NT 201 ranging from 8 to 20 U/kg BW up to a total body dose of 500 U.

Reporting group values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group	Total
Number of subjects	87	88	176	351
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	64	71	136	271
Adolescents (12-17 years)	23	17	40	80
Adults (18-64 years)	0	0	0	0
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	7.2 ± 4.70	7.4 ± 4.13	7.3 ± 4.40	-
Gender categorical
Units: Subjects
Female	38	31	62	131
Male	49	57	114	220
Ethnicity characteristic
Units: Subjects
Hispanic or Latino	16	26	45	87
Not Hispanic or Latino	71	62	131	264
Race characteristic
Units: Subjects
White	81	75	160	316
Black or African American	3	2	2	7
Other	3	11	14	28

End points

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Reporting group title

MP Low Dose Group

Reporting group description

In MP, subjects randomized to low dose group were injected with doses of NT 201 ranging from 2 to 5 Units per kilogram (U/kg) body weight (BW) up to a total body dose of 125 Units (U).

Reporting group title

MP Mid Dose Group

Reporting group description

In MP, subjects randomized to mid dose group were injected with doses of NT 201 ranging from 6 to 15 U/kg BW up to a total body dose of 375 U.

Reporting group title

MP High Dose Group

Reporting group description

In MP, subjects randomized to high dose group were injected with doses of NT 201 ranging from 8 to 20 U/kg BW up to a total body dose of 500 U.

Reporting group title

OLEX (3 Injections)

Reporting group description

Subject analysis set title

MP: Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

The FAS was the subset in the safety analysis set (SES) of the MP for whom the primary efficacy variable or co-primary efficacy variable were available (that is, all subjects who had at least an AS score in the clinical pattern flexed elbow or flexed wrist at baseline [Day 1] or the Investigator’s global impression of change scales [GICS] at Day 29 [Week 4]).

Subject analysis set title

Safety Evaluation Set (SES)

Subject analysis set type

Safety analysis

Subject analysis set description

The SES was the subset of all subjects treated in the MP and OLEX with study medication at least once.

Subject analysis set title

MP Low Dose Group

Subject analysis set type

Safety analysis

Subject analysis set description

In MP, subjects randomized to low dose group were injected with doses of NT 201 ranging from 2 to 5 U/kg BW up to a total body dose of 125 U.

Subject analysis set title

MP Mid Dose Group

Subject analysis set type

Safety analysis

Subject analysis set description

In MP, subjects randomized to mid dose group were injected with doses of NT 201 ranging from 6 to 15 U/kg BW up to a total body dose of 375 U.

Subject analysis set title

MP High Dose Group

Subject analysis set type

Safety analysis

Subject analysis set description

In MP, subjects randomized to high dose group were injected with doses of NT 201 ranging from 8 to 20 U/kg BW up to a total body dose of 500 U.

Subject analysis set title

OLEX (3 Injections)

Subject analysis set type

Safety analysis

Subject analysis set description

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

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End point title

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

End point description

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. Here “n” was the number of subjects who were evaluable for this measure at a given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model.

End point type

Primary

End point timeframe

Baseline and Week 4

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group
Number of subjects analysed	87 ^[1]	87 ^[2]	176 ^[3]
Units: unit on a scale
least squares mean (standard error)
High (n=172) versus Low (n=85)	-0.93 ± 0.078	999 ± 999	-1.15 ± 0.056
Mid (n=86) versus Low (n=85)	-0.96 ± 0.082	-1.02 ± 0.082	999 ± 999

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

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

MP Low Dose Group v MP High Dose Group

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.017

Method

MMRM

Parameter type

LS Mean difference

Point estimate

-0.22

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

-0.04

Statistical Analysis 2

Statistical analysis description

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.

Comparison groups

MP Low Dose Group v MP Mid Dose Group

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.546

Method

MMRM

Parameter type

LS-Mean difference

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

0.15

Primary: Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4

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End point title

Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4

End point description

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. Here “n” was the number of subjects who were evaluable for this measure at given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model.

End point type

Primary

End point timeframe

Week 4

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group
Number of subjects analysed	87 ^[4]	87 ^[5]	176 ^[6]
Units: unit on a scale
least squares mean (standard error)
High (n=176) versus Low (n=87)	1.55 ± 0.083	999 ± 999	1.64 ± 0.062
Mid (n=87) versus Low (n=87)	1.57 ± 0.089	1.44 ± 0.092	999 ± 999

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

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

MP Low Dose Group v MP High Dose Group

Number of subjects included in analysis

263

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.34

Method

ANCOVA

Parameter type

LS-Mean difference

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.28

Statistical Analysis 2

Statistical analysis description

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.

Comparison groups

MP Low Dose Group v MP Mid Dose Group

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.297

Method

ANCOVA

Parameter type

LS-Mean difference

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

0.11

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

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End point title

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

End point description

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. Here “n” was the number of subjects who were evaluable for this measure at given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model.

End point type

Secondary

End point timeframe

Baseline and Week 4

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group
Number of subjects analysed	87 ^[7]	88 ^[8]	176 ^[9]
Units: unit on a scale
least squares mean (standard error)
High (n=143) versus Low (n=67)	-1.03 ± 0.083	999 ± 999	-1.13 ± 0.061
Mid (n=69) versus Low (n=67)	-1.08 ± 0.087	-1.22 ± 0.090	999 ± 999

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

No statistical analyses for this end point

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

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End point title

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

End point description

End point type

Secondary

End point timeframe

Baseline and Week 4

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group
Number of subjects analysed	87 ^[10]	88 ^[11]	176 ^[12]
Units: unit on a scale
least squares mean (standard error)
High (n=45) versus Low (n=18)	-0.53 ± 0.212	999 ± 999	-1.00 ± 0.133
Mid (n=20) versus Low (n=18)	-0.070 ± 0.202	-1.04 ± 0.176	999 ± 999

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

No statistical analyses for this end point

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

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End point title

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

End point description

End point type

Secondary

End point timeframe

Baseline and Week 4

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group
Number of subjects analysed	87 ^[13]	88 ^[14]	176 ^[15]
Units: unit on a scale
least squares mean (standard error)
Flexed elbow: High (n=166) versus Low (n=83)	-0.99 ± 0.076	999 ± 999	-1.18 ± 0.056
Flexed elbow: Mid (n=82) versus Low (n=83)	-1.01 ± 0.081	-1.17 ± 0.082	999 ± 999
Flexed wrist: High (n=149) versus Low (n=69)	-0.96 ± 0.085	999 ± 999	-1.08 ± 0.061
Flexed wrist: Mid (n=73) versus Low (n=69)	-1.01 ± 0.087	-1.05 ± 0.087	999 ± 999
Clenched fist: High (n=64) versus Low (n=34)	-0.64 ± 0.136	999 ± 999	-1.09 ± 0.096
Clenched fist: Mid (n=30) versus Low (n=34)	-0.58 ± 0.145	-0.87 ± 0.141	999 ± 999
Thumb in palm: High (n=98) versus Low (n=49)	-0.88 ± 0.116	999 ± 999	-1.11 ± 0.083
Thumb in palm: Mid (n=44) versus Low (n=49)	-0.93 ± 0.131	-1.14 ± 0.123	999 ± 999
Pronated forearm: High (n=150) versus Low (n=72)	-0.88 ± 0.080	999 ± 999	-1.02 ± 0.058
Pronated forearm: Mid (n=73) versus Low (n=72)	-0.87 ± 0.086	-0.94 ± 0.088	999 ± 999

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

No statistical analyses for this end point

Secondary: MP: Change From Baseline in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) Assessed With 'Questionnaire on Pain caused by Spasticity (QPS)'

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End point title

MP: Change From Baseline in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) Assessed With 'Questionnaire on Pain caused by Spasticity (QPS)'

End point description

Pain intensity (from subjects) 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. Here “n” was the number of subjects who were evaluable for this measure at given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model. P/C = Parent/Caregiver.

End point type

Secondary

End point timeframe

Baseline, Weeks 4, 8, and 14

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group
Number of subjects analysed	87 ^[16]	88 ^[17]	176 ^[18]
Units: unit on a scale
least squares mean (standard error)
UL, Subject, Week 4 High (n=52) versus low (n=30)	-0.42 ± 0.217	999 ± 999	-0.75 ± 0.199
UL, Subject, Week 4 Mid (n=34) versus low (n=30)	-0.39 ± 0.256	-0.67 ± 0.289	999 ± 999
UL, Subject, Week 8 High (n=52) versus low (n=29)	-0.52 ± 0.206	999 ± 999	-0.64 ± 0.188
UL, Subject, Week 8 Mid (n=34) versus low (n=29)	-0.63 ± 0.259	-0.55 ± 0.290	999 ± 999
UL, Subject, Week 14 High (n=52) versus low (n=27)	-0.56 ± 0.217	999 ± 999	-0.59 ± 0.202
UL, Subject, Week 14 Mid (n=32) versus low (n=27)	-0.66 ± 0.327	-0.59 ± 0.361	999 ± 999
UL, P/C, Week 4 High (n=133) versus low (n=64)	-0.46 ± 0.102	999 ± 999	-0.44 ± 0.076
UL, P/C, Week 4 Mid (n=65) versus low (n=64)	-0.43 ± 0.106	-0.28 ± 0.115	999 ± 999
UL, P/C, Week 8 High (n=138) versus low (n=67)	-0.40 ± 0.095	999 ± 999	-0.44 ± 0.070
UL, P/C, Week 8 Mid (n=66) versus low (n=67)	-0.43 ± 0.100	-0.34 ± 0.109	999 ± 999
UL, P/C, Week 14 High (n=137) versus low (n=58)	-0.23 ± 0.105	999 ± 999	-0.24 ± 0.071
UL, P/C, Week 14 Mid (n=61) versus low (n=58)	-0.31 ± 0.100	-0.25 ± 0.107	999 ± 999
LL, Subject, Week 4 High (n=43) versus low (n=24)	-0.74 ± 0.282	999 ± 999	-0.62 ± 0.250
LL, Subject, Week 4 Mid (n=29) versus low (n=24)	-0.46 ± 0.305	-0.55 ± 0.321	999 ± 999
LL, Subject, Week 8 High (n=44) versus low (n=25)	-1.04 ± 0.241	999 ± 999	-0.69 ± 0.218
LL, Subject, Week 8 Mid (n=28) versus low (n=25)	-0.90 ± 0.261	-0.81 ± 0.284	999 ± 999
LL, Subject, Week 14 High (n=43) versus low (n=23)	-0.71 ± 0.275	999 ± 999	-0.57 ± 0.245
LL, Subject, Week 14 Mid (n=28) versus low (n=23)	-0.67 ± 0.315	-0.63 ± 0.335	999 ± 999
LL, P/C, Week 4 High (n=110) versus low (n=56)	-0.50 ± 0.105	999 ± 999	-0.52 ± 0.077
LL, P/C, Week 4 Mid (n=54) versus low (n=56)	-0.46 ± 0.103	-0.42 ± 0.111	999 ± 999
LL, P/C, Week 8 High (n=113) versus low (n=59)	-0.56 ± 0.098	999 ± 999	-0.51 ± 0.074
LL, P/C, Week 8 Mid (n=54) versus low (n=59)	-0.52 ± 0.102	-0.36 ± 0.111	999 ± 999
LL, P/C, Week 14 High (n=110) versus low (n=53)	-0.33 ± 0.108	999 ± 999	-0.32 ± 0.078
LL, P/C, Week 14 Mid (n=53) versus low (n=53)	-0.37 ± 0.086	-0.31 ± 0.090	999 ± 999

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

No statistical analyses for this end point

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

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End point title

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

End point description

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. Here “n” was the number of subjects who were evaluable for this measure at a given time period and were included in the assessment. The value 999 indicates that no data is available from the respective specific model.

End point type

Secondary

End point timeframe

Week 4

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group
Number of subjects analysed	87 ^[19]	88 ^[20]	176 ^[21]
Units: unit on a scale
least squares mean (standard error)
Subject: High (n=55) versus Low (n=31)	1.51 ± 0.153	999 ± 999	1.63 ± 0.139
Subject: Mid (n=38) versus Low (n=31)	1.53 ± 0.180	1.48 ± 0.190	999 ± 999
Parent/Caregiver: High (n=176) versus Low (n=87)	1.41 ± 0.087	999 ± 999	1.60 ± 0.065
Parent/Caregiver: Mid (n=87) versus Low (n=87)	1.36 ± 0.094	1.29 ± 0.097	999 ± 999

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

No statistical analyses for this end point

Secondary: Number of Subjects With Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Treatment Cycle

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End point title

Number of Subjects With Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Treatment Cycle

End point description

The SES was the subset of all subjects treated in the MP and OLEX with study medication at least once. Number of subjects who were evaluable for this measure at a given time period and were included in the assessment.

End point type

Secondary

End point timeframe

Baseline up to Week 66

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group	OLEX (3 Injections)
Number of subjects analysed	87 ^[22]	87 ^[23]	176 ^[24]	331 ^[25]
Units: Subjects
Overall	21	13	42	114
First injection cycle (MP) (n=87,87,176,0)	21	13	42	0
Second injection cycle (OLEX) (n=0,0,0,331)	0	0	0	64
Third injection cycle (OLEX) (n=0,0,0,331)	0	0	0	43
Fourth injection cycle (OLEX) (n=0,0,0,331)	0	0	0	48

Notes
[22] - SES
[23] - SES
[24] - SES
[25] - SES

No statistical analyses for this end point

Secondary: Number of Subjects With Occurrence of TEAEs of Special Interest (TEAESIs) Overall and per Treatment Cycle

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End point title

Number of Subjects With Occurrence of TEAEs of Special Interest (TEAESIs) Overall and per Treatment Cycle

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 66

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group	OLEX (3 Injections)
Number of subjects analysed	87 ^[26]	87 ^[27]	176 ^[28]	331 ^[29]
Units: subjects
Overall	1	1	1	5
First injection cycle (MP) (n=87,87,176,0)	1	1	1	0
Second injection cycle (OLEX) (n=0,0,0,331)	0	0	0	2
Third injection cycle (OLEX) (n=0,0,0,331)	0	0	0	3
Fourth injection cycle (OLEX) (n=0,0,0,331)	0	0	0	1

Notes
[26] - SES
[27] - SES
[28] - SES
[29] - SES

No statistical analyses for this end point

Secondary: Number of Subjects With Occurrence of Serious TEAEs (TESAEs) Overall and per Treatment Cycle

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End point title

Number of Subjects With Occurrence of Serious TEAEs (TESAEs) Overall and per Treatment Cycle

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 66

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group	OLEX (3 Injections)
Number of subjects analysed	87 ^[30]	87 ^[31]	176 ^[32]	331 ^[33]
Units: subjects
Overall	2	1	2	16
First injection cycle (MP) (n=87,87,176,0)	2	1	2	0
Second injection cycle (OLEX) (n=0,0,0,331)	0	0	0	7
Third injection cycle (OLEX) (n=0,0,0,331)	0	0	0	9
Fourth injection cycle (OLEX) (n=0,0,0,331)	0	0	0	3

Notes
[30] - SES
[31] - SES
[32] - SES
[33] - SES

No statistical analyses for this end point

Secondary: Number of Subjects With Occurrence of TEAEs Related to Treatment Overall and per Treatment Cycle

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End point title

Number of Subjects With Occurrence of TEAEs Related to Treatment Overall and per Treatment Cycle

End point description

The SES was the subset of all subjects treated in MP and OLEX with study medication at least once. Number of subjects who were evaluable for this measure at a given time period and were included in the assessment.

End point type

Secondary

End point timeframe

Baseline up to Week 66

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group	OLEX (3 Injections)
Number of subjects analysed	87 ^[34]	87 ^[35]	176 ^[36]	331 ^[37]
Units: subjects
Overall	0	0	3	5
First injection cycle (MP) (n=87,87,176,0)	0	0	3	0
Second injection cycle (OLEX) (n=0,0,0,331)	0	0	0	2
Third injection cycle (OLEX) (n=0,0,0,331)	0	0	0	2
Fourth injection cycle (OLEX) (n=0,0,0,331)	0	0	0	1

Notes
[34] - SES
[35] - SES
[36] - SES
[37] - SES

No statistical analyses for this end point

Secondary: Number of Subjects With Occurrence of TEAEs by Worst Intensity Overall and per Treatment Cycle

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End point title

Number of Subjects With Occurrence of TEAEs by Worst Intensity Overall and per Treatment Cycle

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 66

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group	OLEX (3 Injections)
Number of subjects analysed	87 ^[38]	87 ^[39]	176 ^[40]	331 ^[41]
Units: subjects
Overall: Mild	15	10	33	62
Overall: Moderate	6	2	7	44
Overall: Severe	0	1	2	8
First injection cycle (MP): Mild (n=87,87,176,0)	15	10	33	0
First injection cycle (MP):Moderate(n=87,87,176,0)	6	2	7	0
First injection cycle (MP): Severe (n=87,87,176,0)	0	1	2	0
Second injection cycle (OLEX): Mild (n=0,0,0,331)	0	0	0	43
Second injection cycle(OLEX):Moderate(n=0,0,0,331)	0	0	0	18
Second injection cycle (OLEX): Severe(n=0,0,0,331)	0	0	0	3
Third injection cycle (OLEX): Mild (n=0,0,0,331)	0	0	0	23
Third injection cycle (OLEX):Moderate(n=0,0,0,331)	0	0	0	15
Third injection cycle (OLEX): Severe (n=0,0,0,331)	0	0	0	4
Fourth injection cycle (OLEX): Mild (n=0,0,0,331)	0	0	0	28
Fourth injection cycle(OLEX):Moderate(n=0,0,0,331)	0	0	0	19
Fourth injection cycle (OLEX): Severe(n=0,0,0,331)	0	0	0	1

Notes
[38] - SES
[39] - SES
[40] - SES
[41] - SES

No statistical analyses for this end point

Secondary: Number of Subjects With Occurrence of TEAEs by Worst Causal Relationship Overall and per Treatment Cycle

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End point title

Number of Subjects With Occurrence of TEAEs by Worst Causal Relationship Overall and per Treatment Cycle

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 66

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group	OLEX (3 Injections)
Number of subjects analysed	87 ^[42]	87 ^[43]	176 ^[44]	331 ^[45]
Units: subjects
Overall: Related	0	0	3	5
Overall: Not related	21	13	39	109
First cycle (MP): Related (n=87,87,176,0)	0	0	3	0
First cycle (MP): Not related (n=87,87,176,0)	21	13	39	0
Second cycle (OLEX): Related (n=0,0,0,331)	0	0	0	2
Second cycle (OLEX): Not related (n=0,0,0,331)	0	0	0	62
Third cycle (OLEX): Related (n=0,0,0,331)	0	0	0	2
Third cycle (OLEX): Not related (n=0,0,0,331)	0	0	0	40
Fourth cycle (OLEX): Related (n=0,0,0,331)	0	0	0	1
Fourth cycle (OLEX): Not related (n=0,0,0,331)	0	0	0	47

Notes
[42] - SES
[43] - SES
[44] - SES
[45] - SES

No statistical analyses for this end point

Secondary: Number of Subjects With Occurrence of TEAEs by Final Outcome Overall and per Treatment Cycle

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End point title

Number of Subjects With Occurrence of TEAEs by Final Outcome Overall and per Treatment Cycle

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 66

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group	OLEX (3 Injections)
Number of subjects analysed	87 ^[46]	87 ^[47]	176 ^[48]	331 ^[49]
Units: subjects
Overall: Resolved	18	10	39	96
Overall: Resolved with sequelae	1	0	0	1
Overall: Resolving	0	2	1	7
Overall: Not resolved	2	1	1	8
Overall: Unknown	0	0	1	2
Overall: Fatal	0	0	0	0
First cycle (MP): Resolved (n=87,87,176,0)	18	10	39	0
Firstcycle(MP):Resolvedwithsequelae(n=87,87,176,0)	1	0	0	0
First cycle (MP): Resolving(n=87,87,176,0)	0	2	1	0
First cycle (MP): Not resolved(n=87,87,176,0)	2	1	1	0
First cycle (MP): Unknown(n=87,87,176,0)	0	0	1	0
First cycle (MP): Fatal(n=87,87,176,0)	0	0	0	0
Second cycle (OLEX): Resolved(n=0,0,0,331)	0	0	0	57
Secondcycle(OLEX):Resolvedwithsequelae(n=0,0,0,331	0	0	0	0
Second cycle (OLEX): Resolving(n=0,0,0,331)	0	0	0	3
Second cycle (OLEX): Not resolved(n=0,0,0,331)	0	0	0	4
Second cycle (OLEX): Unknown(n=0,0,0,331)	0	0	0	0
Second cycle (OLEX): Fatal(n=0,0,0,331)	0	0	0	0
Third cycle (OLEX): Resolved(n=0,0,0,331)	0	0	0	37
Thirdcycle(OLEX):Resolvedwithsequelae(n=0,0,0,331)	0	0	0	0
Third cycle (OLEX): Resolving(n=0,0,0,331)	0	0	0	0
Third cycle (OLEX): Not resolved(n=0,0,0,331)	0	0	0	4
Third cycle (OLEX): Unknown(n=0,0,0,331)	0	0	0	1
Third cycle (OLEX): Fatal(n=0,0,0,331)	0	0	0	0
Fourth cycle (OLEX): Resolved(n=0,0,0,331)	0	0	0	39
Fourthcycle(OLEX):Resolvedwithsequelae(n=0,0,0,331	0	0	0	1
Fourth cycle (OLEX): Resolving(n=0,0,0,331)	0	0	0	4
Fourth cycle (OLEX): Not resolved(n=0,0,0,331)	0	0	0	2
Fourth cycle (OLEX): Unknown(n=0,0,0,331)	0	0	0	2
Fourth cycle (OLEX): Fatal(n=0,0,0,331)	0	0	0	0

Notes
[46] - SES
[47] - SES
[48] - SES
[49] - SES

No statistical analyses for this end point

Secondary: Number of Subjects With Occurrence of TEAEs Leading to Discontinuation Overall and per Treatment Cycle

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End point title

Number of Subjects With Occurrence of TEAEs Leading to Discontinuation Overall and per Treatment Cycle

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 66

End point values	MP Low Dose Group	MP Mid Dose Group	MP High Dose Group	OLEX (3 Injections)
Number of subjects analysed	87 ^[50]	87 ^[51]	176 ^[52]	331 ^[53]
Units: subjects
Overall	0	1	1	5
First injection cycle (MP) (n=87,87,176,0)	0	1	1	0
Second injection cycle (OLEX) (n=0,0,0,331)	0	0	0	3
Third injection cycle (OLEX) (n=0,0,0,331)	0	0	0	2
Fourth injection cycle (OLEX) (n=0,0,0,331)	0	0	0	0

Notes
[50] - SES
[51] - SES
[52] - SES
[53] - SES

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to Week 66

Adverse event reporting additional description

The investigator asked the participant for adverse events (AEs) systematically at each visit.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

MP: Low Dose Group

Reporting group description

In MP, subjects randomized to low dose group were injected with doses of NT 201 ranging from 2 to 5 U/kg BW up to a total body dose of 125 U.

Reporting group title

MP: Mid Dose Group

Reporting group description

In MP, subjects randomized to mid dose group were injected with doses of NT 201 ranging from 6 to 15 U/kg BW up to a total body dose of 375 U.

Reporting group title

MP: High Dose Group

Reporting group description

In MP, subjects randomized to high dose group were injected with doses of NT 201 ranging from 8 to 20 U/kg BW up to a total body dose of 500 U.

Reporting group title

OLEX (3 Injections)

Reporting group description

Serious adverse events	MP: Low Dose Group	MP: Mid Dose Group	MP: High Dose Group	OLEX (3 Injections)
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 87 (2.30%)	1 / 87 (1.15%)	2 / 176 (1.14%)	16 / 331 (4.83%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events				0
Injury, poisoning and procedural complications
Shunt malfunction
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
CSF shunt operation
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Electroencephalogram
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Spinal cord neoplasm
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Aspiration
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 176 (0.00%)	0 / 331 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 176 (0.00%)	0 / 331 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain oedema
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 176 (0.00%)	0 / 331 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 87 (1.15%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	2 / 331 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Hiatus hernia
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	2 / 331 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cyclic vomiting syndrome
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 87 (2.30%)	0 / 87 (0.00%)	1 / 176 (0.57%)	0 / 331 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	2 / 176 (1.14%)	0 / 331 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis bacterial
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	1 / 176 (0.57%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pertussis
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	1 / 87 (1.15%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 87 (1.15%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 176 (0.00%)	1 / 331 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	MP: Low Dose Group	MP: Mid Dose Group	MP: High Dose Group	OLEX (3 Injections)
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 87 (5.75%)	3 / 87 (3.45%)	6 / 176 (3.41%)	18 / 331 (5.44%)
Infections and infestations
Nasopharyngitis
subjects affected / exposed	5 / 87 (5.75%)	3 / 87 (3.45%)	6 / 176 (3.41%)	18 / 331 (5.44%)
occurrences all number	5	5	6	22

More information

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Were there any global substantial amendments to the protocol? Yes

24 Apr 2015

Incorporated FDA recommendations based on the draft FDA Guidance for Industry, 'Suicidal ideation and behavior: prospective assessment of occurrence in clinical trials'.

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

Kliiniset tutkimukset Nct sivu

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Primary: Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4

Primary: Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4

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

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

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

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

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

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

Secondary: MP: Change From Baseline in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) Assessed With 'Questionnaire on Pain caused by Spasticity (QPS)'

Secondary: MP: Change From Baseline in Scores of Pain Intensity (From Subjects) and Pain Frequency (From Parent/Caregiver) Assessed With 'Questionnaire on Pain caused by Spasticity (QPS)'

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

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

Secondary: Number of Subjects With Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs of Special Interest (TEAESIs) Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs of Special Interest (TEAESIs) Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of Serious TEAEs (TESAEs) Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of Serious TEAEs (TESAEs) Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs Related to Treatment Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs Related to Treatment Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs by Worst Intensity Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs by Worst Intensity Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs by Worst Causal Relationship Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs by Worst Causal Relationship Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs by Final Outcome Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs by Final Outcome Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs Leading to Discontinuation Overall and per Treatment Cycle

Secondary: Number of Subjects With Occurrence of TEAEs Leading to Discontinuation Overall and per Treatment Cycle

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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