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Clinical Trial Results:
Prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter study with an open-label extension period to investigate the efficacy and safety of NT 201 in the treatment of children and adolescents (2–17 years) with chronic troublesome sialorrhea associated with neurological disorders, and/or intellectual disability

Summary
EudraCT number	2013-004532-30
Trial protocol	HU PL Outside EU/EEA
Global end of trial date	07 May 2019

Results information
Results version number	v1(current)
This version publication date	20 Nov 2019
First version publication date	20 Nov 2019
Other versions

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_3091_1

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Merz Pharmaceuticals GmbH

Sponsor organisation address

Eckenheimer Landstrasse 100, Frankfurt/Main, Germany, 60318

Public contact

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

Scientific contact

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

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001039-PIP02-12

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

07 May 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

07 May 2019

Was the trial ended prematurely?

Main objective of the trial

The objective of this study is to investigate the efficacy and safety of NT 201 compared with placebo for the treatment of chronic troublesome sialorrhea associated with neurological disorders (example cerebral palsy, traumatic brain injury) and/or intellectual disability in children and adolescents naive to Botulinum neurotoxin treatment and aged 2–17 years.

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 subject safety while the study was ongoing.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Feb 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 51

Country: Number of subjects enrolled

Hungary: 13

Country: Number of subjects enrolled

Ukraine: 121

Country: Number of subjects enrolled

Georgia: 25

Country: Number of subjects enrolled

Russian Federation: 44

Country: Number of subjects enrolled

Serbia: 1

Worldwide total number of subjects

255

EEA total number of subjects

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)

179

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 investigational sites in Georgia, Hungary, Poland, Russia, Serbia, and Ukraine.

Screening details

A total of 281 subjects were screened, out of which 256 subjects were randomized/assigned into the study. Of these 256 subjects, 255 subjects received the study treatment. A total of 247 subjects who completed the Main Period (MP) entered the Open-label Extension Period (OLEX) of the study.

Period 1 title

Main Period (MP)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Subject, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Double-blind MP: Placebo (age 6 to 17 years)

Arm description

Subjects received placebo via bilateral intraglandular injection into the parotid and submandibular glands in one injection session on Day 1 (Visit 2) of the MP, followed by an observation period of 16 weeks. Volumes were matched to the volumes of NT 201 (incobotulinumtoxinA; Xeomin) injected in the experimental arm.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intraglandular use

Dosage and administration details

Double-blind, MP: NT 201 (age 6 to 17 years)

Arm description

Subjects received NT 201 (up to 2.5 Units per kilogram [U/kg] body weight) via bilateral intraglandular injection into the parotid and submandibular glands in one injection session on Day 1 (Visit 2) of the MP, followed by an observation period of 16 weeks.

Arm type

Experimental

Investigational medicinal product name

IncobotulinumtoxinA

Investigational medicinal product code

NT 201

Other name

Xeomin; Incobotulinumtoxin A; Botulinum neurotoxin type A free from complexing proteins

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intraglandular use

Dosage and administration details

Subjects received NT 201 (up to 2.5 U/kg body weight) via bilateral intraglandular injection into the parotid and submandibular glands in one injection session on Day 1 (Visit 2) of the MP, followed by an observation period of 16 weeks.

Open-label, MP: NT 201 (age 2 to 5 years)

Arm description

Subjects received NT 201 (about 1.5-2 U/kg body weight) via bilateral intraglandular injection into the parotid and submandibular glands in one injection session on Day 1 (Visit 2) of the MP, followed by an observation period of 16 weeks.

Arm type

Experimental

Investigational medicinal product name

IncobotulinumtoxinA

Investigational medicinal product code

NT 201

Other name

Xeomin; Incobotulinumtoxin A; Botulinum neurotoxin type A free from complexing proteins

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intraglandular use

Dosage and administration details

Number of subjects in period 1	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)	Open-label, MP: NT 201 (age 2 to 5 years)
Started	72	148	35
Completed	70	146	34
Not completed	2	2	1
Consent withdrawn by subject	2	-	1
Adverse event, non-fatal	-	1	-
Lost to follow-up	-	1	-

Period 2 title

Open-label Extension Period (OLEX)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

OLEX: NT 201 (age 6 to 17 years)

Arm description

Subjects received NT 201 (up to 2.5 U/kg body weight) via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 of second (Visit 6), third (Visit 10), and fourth (Visit 14) injection cycle of the OLEX, followed by an observation period of 16 weeks each (48 weeks in total). This arm consisted of subjects who participated in MP arms “Double-blind, MP: placebo (age 6 to 17 years)” and “Double-blind, MP: NT 201 (age 6 to 17 years)”.

Arm type

Experimental

Investigational medicinal product name

IncobotulinumtoxinA

Investigational medicinal product code

NT 201

Other name

Xeomin; Incobotulinumtoxin A; Botulinum neurotoxin type A free from complexing proteins

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intraglandular use

Dosage and administration details

OLEX: NT 201 (age 2 to 5 years)

Arm description

Subjects received NT 201 (about 1.5-2 U/kg body weight) via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 of second (Visit 6), third (Visit 10), and fourth (Visit 14) injection cycle of the OLEX, followed by an observation period of 16 weeks each (48 weeks in total).

Arm type

Experimental

Investigational medicinal product name

IncobotulinumtoxinA

Investigational medicinal product code

NT 201

Other name

Xeomin; Incobotulinumtoxin A; Botulinum neurotoxin type A free from complexing proteins

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intraglandular use

Dosage and administration details

Number of subjects in period 2 ^[1]	OLEX: NT 201 (age 6 to 17 years)	OLEX: NT 201 (age 2 to 5 years)
Started	214	33
Completed	189	33
Not completed	25	0
Consent withdrawn by subject	16	-
Physician decision	1	-
Adverse event, non-fatal	4	-
Lost to follow-up	2	-
Lack of efficacy	2	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 3 subjects, 1 in each MP treatment group, did not enter the OLEX due to AE(s) (1 subject) and withdrawal of consent (2 subjects).

Baseline characteristics

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Reporting group title

Double-blind MP: Placebo (age 6 to 17 years)

Reporting group description

Reporting group title

Double-blind, MP: NT 201 (age 6 to 17 years)

Reporting group description

Reporting group title

Open-label, MP: NT 201 (age 2 to 5 years)

Reporting group description

Reporting group values	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)	Open-label, MP: NT 201 (age 2 to 5 years)	Total
Number of subjects	72	148	35	255
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)	48	96	35	179
Adolescents (12-17 years)	24	52	0	76
Adults (18-64 years)	0	0	0	0
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Gender categorical
Units: Subjects
Female	27	55	13	95
Male	45	93	22	160
Race characteristic
Units: Subjects
White	72	148	35	255
Height characteristic
Units: centimeter (cm)
arithmetic mean (standard deviation)	135.3 ( 16.92 )	132.8 ( 17.15 )	101.1 ( 8.09 )	-
Weight characteristic
Units: kilogram (kg)
arithmetic mean (standard deviation)	30.8 ( 11.67 )	28.8 ( 11.48 )	15.7 ( 3.00 )	-
Body Mass Index (BMI)
Units: kilogram per square meter (kg/m^2)
arithmetic mean (standard deviation)	16.4 ( 3.65 )	15.8 ( 3.25 )	15.3 ( 1.85 )	-

End points

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Reporting group title

Double-blind MP: Placebo (age 6 to 17 years)

Reporting group description

Reporting group title

Double-blind, MP: NT 201 (age 6 to 17 years)

Reporting group description

Reporting group title

Open-label, MP: NT 201 (age 2 to 5 years)

Reporting group description

Reporting group title

OLEX: NT 201 (age 6 to 17 years)

Reporting group description

Reporting group title

OLEX: NT 201 (age 2 to 5 years)

Reporting group description

Subject analysis set title

MP: Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

The FAS is identical to the subset of subjects in the safety evaluation set of the MP (SES [MP]). The SES (MP) is the subset of all subjects who received study medication (NT 201 or placebo) during the MP of the study.

Subject analysis set title

MP: SES

Subject analysis set type

Safety analysis

Subject analysis set description

The SES (MP) is the subset of all subjects who received study medication (NT 201 or placebo) during the MP of the study.

Subject analysis set title

OLEX: SES

Subject analysis set type

Safety analysis

Subject analysis set description

The SES of the OLEX is the subset of all subjects who received study medication (NT 201) at least once during the OLEX of the study.

Primary: Change From Baseline in Unstimulated Salivary Flow Rate (uSFR) at Week 4

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End point title

Change From Baseline in Unstimulated Salivary Flow Rate (uSFR) at Week 4 ^[1]

End point description

This endpoint was analysed in double-blind, MP, 6 to 17 years subjects. uSFR was assessed by weighing of absorbent swabs with safety threads soaked with saliva over 5 minutes and the procedure was repeated after 30 minutes. Salivary flow rate was equal to weight increase of swabs/time of collection. The average of the 2 results for flow rate was calculated. The reduction of measured weight over the study relates to improvement of sialorrhea.

End point type

Primary

End point timeframe

Baseline and Week 4

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to be analysed only for two reporting groups: Double-blind MP: Placebo (age 6 to 17 years) and Double-blind, MP: NT 201 (age 6 to 17 years).

End point values	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)
Number of subjects analysed	72 ^[2]	148 ^[3]
Units: gram per minute (g/min)
least squares mean (standard error)	-0.07 ( 0.015 )	-0.14 ( 0.012 )

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

Statistical Analysis 1

Statistical analysis description

Least square mean (LS-Mean) is from a mixed model repeated measurement (MMRM) analysis with treatment group, pooled investigation sites, and age groups as fixed factors, visit*treatment as interaction term, visit as repeated factor, and baseline uSFR score as covariate.

Comparison groups

Double-blind MP: Placebo (age 6 to 17 years) v Double-blind, MP: NT 201 (age 6 to 17 years)

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0012

Method

MMRM

Parameter type

LS-Mean difference

Point estimate

-0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

-0.03

Variability estimate

Standard error of the mean

Dispersion value

0.019

Primary: Global Impression of Change Scale (GICS) at Week 4 Assessed by the Carer/Parent(s)

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End point title

Global Impression of Change Scale (GICS) at Week 4 Assessed by the Carer/Parent(s) ^[4]

End point description

This endpoint was analysed in double-blind, MP, 6 to 17 years subjects. The GICS was used to measure the carer's/parent's impression of change due to treatment. The response option was a common 7-point Likert scale, with the following values: +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse).

End point type

Primary

End point timeframe

Week 4

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to be analysed only for two reporting groups: Double-blind MP: Placebo (age 6 to 17 years) and Double-blind, MP: NT 201 (age 6 to 17 years).

End point values	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)
Number of subjects analysed	72 ^[5]	148 ^[6]
Units: units on a scale
least squares mean (standard error)	0.63 ( 0.104 )	0.91 ( 0.075 )

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

Statistical Analysis 1

Statistical analysis description

LS-Mean is from a MMRM analysis model with treatment group, pooled investigation sites, and age groups as fixed factors, visit*treatment as interaction term, visit as repeated factor, and baseline Modified Teacher Drooling Scale (mTDS) score as covariate.

Comparison groups

Double-blind MP: Placebo (age 6 to 17 years) v Double-blind, MP: NT 201 (age 6 to 17 years)

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.032

Method

MMRM

Parameter type

LS-Mean difference

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.53

Variability estimate

Standard error of the mean

Dispersion value

0.127

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

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End point title

Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and per Treatment Cycle ^[7]

End point description

“n” is the number of subjects evaluable for this measure at a given time period and who were included in the assessment.

End point type

Primary

End point timeframe

Baseline up to Week 64

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analysed for this endpoint.

End point values	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)	Open-label, MP: NT 201 (age 2 to 5 years)	OLEX: NT 201 (age 6 to 17 years)	OLEX: NT 201 (age 2 to 5 years)
Number of subjects analysed	72 ^[8]	148 ^[9]	35 ^[10]	214 ^[11]	33 ^[12]
Units: subjects
Overall (n=72,148,35,214,33)	11	27	5	92	15
First injection cycle (MP) (n=72,148,35,0,0)	11	27	5	0	0
Second injection cycle (OLEX) (n=0,0,0,214,33)	0	0	0	44	7
Third injection cycle (OLEX) (n=0,0,0,205,33)	0	0	0	35	5
Fourth injection cycle (OLEX) (n=0,0,0,193,33)	0	0	0	40	11

Notes
[8] - MP-SES
[9] - MP-SES
[10] - MP-SES
[11] - OLEX-SES
[12] - OLEX-SES

No statistical analyses for this end point

Secondary: Change From Baseline in uSFR at Weeks 8 and 12

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End point title

Change From Baseline in uSFR at Weeks 8 and 12 ^[13]

End point description

This endpoint was analysed in double-blind, MP, 6 to 17 years subjects. uSFR was assessed by weighing of absorbent swabs with safety threads soaked with saliva over 5 minutes and then procedure was repeated after 30 minutes. Salivary flow rate was equal to weight increase of swabs/time of collection. The average of the 2 results for flow rate was calculated. The reduction of measured weight over the study relates to improvement of sialorrhea.

End point type

Secondary

End point timeframe

Baseline and Weeks 8 and 12

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to be analysed only for two reporting groups: Double-blind MP: Placebo (age 6 to 17 years) and Double-blind, MP: NT 201 (age 6 to 17 years).

End point values	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)
Number of subjects analysed	72 ^[14]	148 ^[15]
Units: g/min
least squares mean (standard error)
Change at Week 8	-0.07 ( 0.015 )	-0.16 ( 0.012 )
Change at Week 12	-0.06 ( 0.016 )	-0.16 ( 0.013 )

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

Statistical Analysis at Week 8

Statistical analysis description

LS-Mean is from a MMRM analysis with treatment group, pooled investigation sites, and age groups as fixed factors, visit*treatment as interaction term, visit as repeated factor, and baseline uSFR score as covariate.

Comparison groups

Double-blind MP: Placebo (age 6 to 17 years) v Double-blind, MP: NT 201 (age 6 to 17 years)

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

MMRM

Parameter type

LS-Mean difference

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.12

upper limit

-0.05

Variability estimate

Standard error of the mean

Dispersion value

0.019

Statistical Analysis at Week 12

Statistical analysis description

Comparison groups

Double-blind MP: Placebo (age 6 to 17 years) v Double-blind, MP: NT 201 (age 6 to 17 years)

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

MMRM

Parameter type

LS-Mean difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

-0.06

Variability estimate

Standard error of the mean

Dispersion value

0.021

Secondary: GICS at Weeks 8 and 12

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End point title

GICS at Weeks 8 and 12 ^[16]

End point description

This endpoint was analysed in double-blind, MP, 6 to 17 years subjects. The GICS was used to measure the carer's/parent's impression of change due to treatment. The response option was a common 7-point Likert scale with the following values: +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse).

End point type

Secondary

End point timeframe

Baseline and Weeks 8 and 12

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to be analysed only for two reporting groups: Double-blind MP: Placebo (age 6 to 17 years) and Double-blind, MP: NT 201 (age 6 to 17 years).

End point values	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)
Number of subjects analysed	72 ^[17]	148 ^[18]
Units: units on a scale
least squares mean (standard error)
Week 8	0.54 ( 0.096 )	0.94 ( 0.068 )
Week 12	0.47 ( 0.111 )	0.87 ( 0.073 )

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

Statistical Analysis at Week 8

Statistical analysis description

Comparison groups

Double-blind MP: Placebo (age 6 to 17 years) v Double-blind, MP: NT 201 (age 6 to 17 years)

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0008

Method

MMRM

Parameter type

LS-Mean difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

0.63

Variability estimate

Standard error of the mean

Dispersion value

0.116

Statistical Analysis at Week 12

Statistical analysis description

Comparison groups

Double-blind MP: Placebo (age 6 to 17 years) v Double-blind, MP: NT 201 (age 6 to 17 years)

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0026

Method

MMRM

Parameter type

LS-Mean difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.14

upper limit

0.66

Variability estimate

Standard error of the mean

Dispersion value

0.132

Secondary: Occurrence of Treatment Emergent Adverse Events of Special Interest (AESI) Overall and by Injection Cycle

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End point title

Occurrence of Treatment Emergent Adverse Events of Special Interest (AESI) Overall and by Injection Cycle

End point description

“n” is the number of subjects evaluable for this measure at a given time period and who were included in the assessment.

End point type

Secondary

End point timeframe

Baseline up to Week 64

End point values	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)	Open-label, MP: NT 201 (age 2 to 5 years)	OLEX: NT 201 (age 6 to 17 years)	OLEX: NT 201 (age 2 to 5 years)
Number of subjects analysed	72 ^[19]	148 ^[20]	35 ^[21]	214 ^[22]	33 ^[23]
Units: subjects
Overall (n=72,148,35,214,33)	0	1	0	4	0
First injection cycle (MP) (n=72,148,35,0,0)	0	1	0	0	0
Second injection cycle (OLEX) (n=0,0,0,214,33)	0	0	0	3	0
Third injection cycle (OLEX) (n=0,0,0,205,33)	0	0	0	1	0
Fourth injection cycle (OLEX) (n=0,0,0,193,33)	0	0	0	0	0

Notes
[19] - MP-SES
[20] - MP-SES
[21] - MP-SES
[22] - OLEX-SES
[23] - OLEX-SES

No statistical analyses for this end point

Secondary: Occurrence of Treatment Emergent Serious Adverse Events (TESAEs) Overall and by Injection Cycle

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End point title

Occurrence of Treatment Emergent Serious Adverse Events (TESAEs) Overall and by Injection Cycle

End point description

“n” is the number of subjects evaluable for this measure at a given time period and who were included in the assessment.

End point type

Secondary

End point timeframe

Baseline up to Week 64

End point values	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)	Open-label, MP: NT 201 (age 2 to 5 years)	OLEX: NT 201 (age 6 to 17 years)	OLEX: NT 201 (age 2 to 5 years)
Number of subjects analysed	72 ^[24]	148 ^[25]	35 ^[26]	214 ^[27]	33 ^[28]
Units: subjects
Overall (n=72,148,35,214,33)	1	0	1	8	0
First injection cycle (MP) (n=72,148,35,0,0)	1	0	1	0	0
Second injection cycle (OLEX) (n=0,0,0,214,33)	0	0	0	3	0
Third injection cycle (OLEX) (n=0,0,0,205,33)	0	0	0	5	0
Fourth injection cycle (OLEX) (n=0,0,0,193,33)	0	0	0	0	0

Notes
[24] - MP-SES
[25] - MP-SES
[26] - MP-SES
[27] - OLEX-SES
[28] - OLEX-SES

No statistical analyses for this end point

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

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End point title

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

End point description

“n” is the number of subjects evaluable for this measure at a given time period and who were included in the assessment.

End point type

Secondary

End point timeframe

Baseline up to Week 64

End point values	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)	Open-label, MP: NT 201 (age 2 to 5 years)	OLEX: NT 201 (age 6 to 17 years)	OLEX: NT 201 (age 2 to 5 years)
Number of subjects analysed	72 ^[29]	148 ^[30]	35 ^[31]	214 ^[32]	33 ^[33]
Units: subjects
Overall (n=72,148,35,214,33)	0	2	1	10	0
First injection cycle (MP) (n=72,148,35,0,0)	0	2	1	0	0
Second injection cycle (OLEX) (n=0,0,0,214,33)	0	0	0	5	0
Third injection cycle (OLEX) (n=0,0,0,205,33)	0	0	0	5	0
Fourth injection cycle (OLEX) (n=0,0,0,193,33)	0	0	0	1	0

Notes
[29] - MP-SES
[30] - MP-SES
[31] - MP-SES
[32] - OLEX-SES
[33] - OLEX-SES

No statistical analyses for this end point

Secondary: Occurrence of TEAEs Leading to Discontinuation Overall and by Injection Cycle

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End point title

Occurrence of TEAEs Leading to Discontinuation Overall and by Injection Cycle

End point description

“n” is the number of subjects evaluable for this measure at a given time period and who were included in the assessment.

End point type

Secondary

End point timeframe

Baseline up to Week 64

End point values	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)	Open-label, MP: NT 201 (age 2 to 5 years)	OLEX: NT 201 (age 6 to 17 years)	OLEX: NT 201 (age 2 to 5 years)
Number of subjects analysed	72 ^[34]	148 ^[35]	35 ^[36]	214 ^[37]	33 ^[38]
Units: subjects
Overall (n=72,148,35,214,33)	1	1	1	4	0
First injection cycle (MP) (n=72,148,35,0,0)	1	1	1	0	0
Second injection cycle (OLEX) (n=0,0,0,214,33)	0	0	0	2	0
Third injection cycle (OLEX) (n=0,0,0,205,33)	0	0	0	2	0
Fourth injection cycle (OLEX) (n=0,0,0,193,33)	0	0	0	0	0

Notes
[34] - MP-SES
[35] - MP-SES
[36] - MP-SES
[37] - OLEX-SES
[38] - OLEX-SES

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to Week 64

Adverse event reporting additional description

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

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Double-blind MP: Placebo (age 6 to 17 years)

Reporting group description

Reporting group title

Double-blind, MP: NT 201 (age 6 to 17 years)

Reporting group description

Reporting group title

Open-label, MP: NT 201 (age 2 to 5 years)

Reporting group description

Reporting group title

OLEX: NT 201 (age 6 to 17 years)

Reporting group description

Reporting group title

OLEX: NT 201 (age 2 to 5 years)

Reporting group description

Serious adverse events	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)	Open-label, MP: NT 201 (age 2 to 5 years)	OLEX: NT 201 (age 6 to 17 years)	OLEX: NT 201 (age 2 to 5 years)
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 72 (1.39%)	0 / 148 (0.00%)	1 / 35 (2.86%)	8 / 214 (3.74%)	0 / 33 (0.00%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Injury, poisoning and procedural complications
Foreign body in gastrointestinal tract
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Gastric operation
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	1 / 35 (2.86%)	0 / 214 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 72 (1.39%)	0 / 148 (0.00%)	0 / 35 (0.00%)	0 / 214 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Functional gastrointestinal disorder
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	2 / 214 (0.93%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Limb deformity
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Staphylococcal bacteraemia
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	1 / 35 (2.86%)	0 / 214 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 72 (1.39%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Double-blind MP: Placebo (age 6 to 17 years)	Double-blind, MP: NT 201 (age 6 to 17 years)	Open-label, MP: NT 201 (age 2 to 5 years)	OLEX: NT 201 (age 6 to 17 years)	OLEX: NT 201 (age 2 to 5 years)
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 72 (4.17%)	3 / 148 (2.03%)	2 / 35 (5.71%)	34 / 214 (15.89%)	12 / 33 (36.36%)
Infections and infestations
Nasopharyngitis
subjects affected / exposed	3 / 72 (4.17%)	3 / 148 (2.03%)	2 / 35 (5.71%)	13 / 214 (6.07%)	1 / 33 (3.03%)
occurrences all number	3	3	3	16	1
Pharyngitis
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	12 / 214 (5.61%)	3 / 33 (9.09%)
occurrences all number	0	0	0	13	3
Respiratory tract infection
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	6 / 214 (2.80%)	3 / 33 (9.09%)
occurrences all number	0	0	0	6	4
Viral infection
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	4 / 214 (1.87%)	2 / 33 (6.06%)
occurrences all number	0	0	0	7	3
Respiratory tract infection viral
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	1 / 214 (0.47%)	4 / 33 (12.12%)
occurrences all number	0	0	0	2	5
Rhinitis
subjects affected / exposed	0 / 72 (0.00%)	0 / 148 (0.00%)	0 / 35 (0.00%)	2 / 214 (0.93%)	3 / 33 (9.09%)
occurrences all number	0	0	0	2	4

More information

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Were there any global substantial amendments to the protocol? Yes

04 May 2015

The draft FDA guidance for Industry, ‘Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials’ was incorporated.

16 Jun 2016

The confirmatory primary analysis was changed from an analysis of covariance (ANCOVA) with missing value replacement strategy (baseline observation carried forward [BOCF] approach) to an MMRM approach for primary and secondary efficacy variables analysis, and exclusion criteria were updated.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Unstimulated Salivary Flow Rate (uSFR) at Week 4

Primary: Change From Baseline in Unstimulated Salivary Flow Rate (uSFR) at Week 4

Primary: Global Impression of Change Scale (GICS) at Week 4 Assessed by the Carer/Parent(s)

Primary: Global Impression of Change Scale (GICS) at Week 4 Assessed by the Carer/Parent(s)

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

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

Secondary: Change From Baseline in uSFR at Weeks 8 and 12

Secondary: Change From Baseline in uSFR at Weeks 8 and 12

Secondary: GICS at Weeks 8 and 12

Secondary: GICS at Weeks 8 and 12

Secondary: Occurrence of Treatment Emergent Adverse Events of Special Interest (AESI) Overall and by Injection Cycle

Secondary: Occurrence of Treatment Emergent Adverse Events of Special Interest (AESI) Overall and by Injection Cycle

Secondary: Occurrence of Treatment Emergent Serious Adverse Events (TESAEs) Overall and by Injection Cycle

Secondary: Occurrence of Treatment Emergent Serious Adverse Events (TESAEs) Overall and by Injection Cycle

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

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

Secondary: Occurrence of TEAEs Leading to Discontinuation Overall and by Injection Cycle

Secondary: Occurrence of TEAEs Leading to Discontinuation Overall and by Injection Cycle

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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