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Clinical Trial Results:
A randomised, multinational, active-controlled,(open-labelled), dose finding, (double-blinded), parallel group trial investigating efficacy and safety of once-weekly NNC0195-0092 treatment compared to daily growth hormone treatment (Norditropin® FlexPro®) in growth hormone treatment naïve pre-pubertal children with growth hormone deficiency

Summary
EudraCT number	2015-000531-32
Trial protocol	AT SE SI DE BE
Global end of trial date	26 Sep 2024

Results information
Results version number	v1(current)
This version publication date	11 Apr 2025
First version publication date	11 Apr 2025
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

NN8640-4172

ISRCTN number

US NCT number

NCT02616562

WHO universal trial number (UTN)

U1111-1166-7062

Sponsor organisation name

Novo Nordisk A/S

Sponsor organisation address

Novo Alle, Bagsvaerd, Denmark, 2880

Public contact

Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com

Scientific contact

Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com

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

15 Nov 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Sep 2024

Was the trial ended prematurely?

Main objective of the trial

Cohort I: To evaluate the efficacy of multiple dose regiments of once-weekly somapacitan after 26 weeks of treatment in Growth Hormone (GH) treatment naive pre-pubertal children with Growth hormone deficiency (GHD) compared to once-daily human growth hormone (hGH) administration (Norditropin Flexpro) Cohort II and III: To evaluate the safety of once-weekly somapacitan during up to 208 weeks of treatment in children with GHD.

Protection of trial subjects

The trial was conducted in accordance with the Declaration of Helsinki (Oct 2013) and International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents, (May 1996) and 21 Code of Federal Regulations (CFR) 312.120.

Background therapy

Not applicable

Evidence for comparator

Actual start date of recruitment

23 Mar 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

4 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Brazil: 1

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

India: 14

Country: Number of subjects enrolled

Israel: 8

Country: Number of subjects enrolled

Japan: 17

Country: Number of subjects enrolled

Slovenia: 3

Country: Number of subjects enrolled

Sweden: 3

Country: Number of subjects enrolled

Türkiye: 2

Country: Number of subjects enrolled

Ukraine: 7

Country: Number of subjects enrolled

United States: 15

Worldwide total number of subjects

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)

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 trial was conducted at 30 sites in 11 countries.

Screening details

Subjects (cohort I) given somapacitan/Norditropin in main & extension period & safety extension period. After which (from week 156), all subjects were given somapacitan for long-term safety extension period. Subjects in cohorts II and III were given somapacitan from enrolment (week 156).

Period 1 title

Main and Extension period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

The main & extension trial period was double-blinded with regard to different dose levels of somapacitan but open-labelled with regard to daily Norditropin as active control arm.

Are arms mutually exclusive

Yes

Cohort I Norditropin/somapacitan

Arm description

Subjects received Norditropin 0.034 miligram per kilogram (mg/kg) subcutaneously once weekly during (26 week) main trial period and (26 week) extension trial period.

Arm type

Experimental

Investigational medicinal product name

Norditropin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Norditropin 0.034mg/kg was given subcutaneously daily from week 0 to week 52

Cohort I somapacitan pooled

Arm description

Subjects were randomized (1:1:1) to receive somapacitan treatment (0.04/0.08/0.16 mg/kg/week) subcutaneously once-weekly during the (26 week) main trial period and (26 week) extension trial period.

Arm type

Experimental

Investigational medicinal product name

somapacitan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

somapacitan 0.04/0.08/0.16mg was given subcutaneously once weekly from week 0 to week 52.

Number of subjects in period 1 ^[1]	Cohort I Norditropin/somapacitan	Cohort I somapacitan pooled
Started	14	45
Completed	14	44
Not completed	0	1
Withdrawl by parent/guardian	-	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The worldwide number of subjects enrolled in the trial are 76. 17 participants entered the trial in the long-term safety extension period and hence are not a part of the baseline period

Period 2 title

Safety extension priod

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

After week 52, the trial was open-labelled with one dose level of somapacitan and Norditropin.

Are arms mutually exclusive

Yes

Cohort I Norditropin/somapacitan

Arm description

Subjects received Norditropin 0.034 miligram per kilogram (mg/kg) subcutaneously once weekly during (104 week) safety extension period.

Arm type

Experimental

Investigational medicinal product name

Norditropin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Norditropin 0.034mg/kg was given subcutaneously daily from week 52 to week 156

Cohort I somapacitan pooled

Arm description

Subjects initially randomized to double-blinded somapacitan treatment 0.04/0.08/0.16mg/kg/week during main and extension period received open-labelled somapacitan treatment 0.16 mg/kg/week subcutaneously once-weekly during 104 week safety extension period.

Arm type

Experimental

Investigational medicinal product name

somapacitan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

somapacitan 0.16mg/kg was given subcutaneously once weekly from week 52 to week 156.

Number of subjects in period 2	Cohort I Norditropin/somapacitan	Cohort I somapacitan pooled
Started	14	44
Completed	12	41
Not completed	2	3
Withdrawl by parent/guardian	-	1
treatment discontinued before visit 5	1	1
Lost to follow-up	-	1
Protocol deviation	1	-

Period 3 title

Long term safety extension period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

After week 156, the trial was open-labelled with one dose level of somapacitan.

Are arms mutually exclusive

Cohort I Norditropin/somapacitan

Arm description

Subjects who received Norditropin until week 156 were given somapacitan 0.16 mg/kg subcutaneously once weekly for the 208-week long terms safety extension period (up till week 364)

Arm type

Experimental

Investigational medicinal product name

somapacitan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

somapacitan 0.16 mg/kg was given subcutaneously once weekly from week 156 to week 364

Cohort I somapacitan pooled

Arm description

Subjects received somapacitan 0.16 mg/kg subcutaneously once weekly for the 208-week long terms safety extension period (up till week 364)

Arm type

Experimental

Investigational medicinal product name

somapacitan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

somapacitan 0.16 mg/kg was given subcutaneously once weekly from week 156 to week 364

Cohort II somapacitan previously treated

Arm description

Subject who was previously treated with GH (Growth hormone) prior to enrollment in the trial at week 156, received somapacitan 0.16mg/kg subcutaneously once weekly until it is available for prescription in subjects' respective countries or until August 2024, at the latest.

Arm type

Experimental

Investigational medicinal product name

somapacitan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

somapacitan 0.16 mg/kg given subcutaneously once weekly from week 156 until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Cohort III somapacitan treatment naive

Arm description

Subjects who were naive to treatment with GH prior to enrollment in the trial at week 156, received open-labelled somapacitan 0.16mg/kg subcutaneously once weekly until it is available for prescription in subjects' respective countries or until August 2024, at the latest.

Arm type

Experimental

Investigational medicinal product name

somapacitan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

somapacitan 0.16 mg/kg given subcutaneously once weekly from week 156 until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Cohort III somapacitan previously treated

Arm description

Subjects who were previously treated with GH prior to enrollment in the trial at week 156, received open-labelled somapacitan 0.16mg/kg subcutaneously once weekly until it is available for prescription in subjects' respective countries or until August 2024, at the latest.

Arm type

Experimental

Investigational medicinal product name

somapacitan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

somapacitan 0.16 mg/kg given subcutaneously once weekly from week 156 until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Number of subjects in period 3	Cohort I Norditropin/somapacitan	Cohort I somapacitan pooled	Cohort II somapacitan previously treated	Cohort III somapacitan treatment naive	Cohort III somapacitan previously treated
Started	12	41	1	4	12
Completed	10	33	1	2	9
Not completed	2	8	0	2	3
Withdrawl by parent/guardian	-	4	-	-	1
Consent withdrawn by subject	1	-	-	1	1
Subject was discontinued from trial	-	1	-	-	-
Lost to follow up	-	-	-	1	-
Adult height reached	-	-	-	-	1
Growth velocity in 9 months is 1 cm (1.3 CM/Y)	1	-	-	-	-
adverse event	-	1	-	-	-
Principal Investigator's decision	-	1	-	-	-
Protocol deviation	-	1	-	-	-

Period 4 title

Extension after week 364

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

After week 156, the trial was open-labelled with one dose level of somapacitan.

Are arms mutually exclusive

Yes

Cohort I Norditropin/somapacitan

Arm description

Subjects received somapacitan 0.16 mg/kg subcutaneously once weekly until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Arm type

Experimental

Investigational medicinal product name

somapacitan

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection, Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

somapacitan 0.16 mg/kg given subcutaneously once weekly from week 364 until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Cohort I somapacitan pooled

Arm description

Subjects received somapacitan 0.16 mg/kg subcutaneously once weekly until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Arm type

Experimental

Investigational medicinal product name

somapacitan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

somapacitan 0.16 mg/kg given subcutaneously once weekly from week 364 until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Number of subjects in period 4	Cohort I Norditropin/somapacitan	Cohort I somapacitan pooled
Started	10	33
Completed	5	17
Not completed	5	16
Somapacitan available in their country	5	16

Baseline characteristics

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Reporting group title

Main and Extension period

Reporting group description

In Cohort I Norditropin/somapacitan arm subjects received Norditropin 0.034 miligram per kilogram (mg/kg) subcutaneously once weekly during (26 week) main trial period and (26 week) extension trial period. And in Cohort I somapacitan pooled arm subjects were randomized (1:1:1) to receive somapacitan treatment (0.04/0.08/0.16 mg/kg) subcutaneously once-weekly during the (26 week) main trial period and (26 week) extension trial period.

Reporting group values	Main and Extension period	Total
Number of subjects	59	59
Age Categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	59	59
Adolescents (12-17 years)	0	0
Adults (18-64 years)	0	0
From 65-84 years	0	0
85 years and over	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	5.84 ( 1.94 )	-
Gender Categorical
Units: Subjects
Female	23	23
Male	36	36

Subject analysis set title

Norditropin 0.034 mg/kg/day

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received Norditropin 0.034 mg/kg subcutaneously daily during 26 weeks main trial period.

Subject analysis set title

somapacitan 0.04mg/kg/week

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received somapacitan 0.04 mg/kg subcutaneously once weekly during 26 weeks main trial period.

Subject analysis set title

somapaciatn 0.08mg/kg/week

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received somapacitan 0.08 mg/kg subcutaneously once weekly during 26 weeks main trial period.

Subject analysis set title

somapcitan 0.16mg/kg/week

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received somapacitan 0.16 mg/kg subcutaneously once weekly during 26 weeks main trial period.

Subject analysis set title

Norditropin 0.034mg/kg/day 0-156 week Cohort I

Subject analysis set type

Full analysis

Subject analysis set description

Subjects were randomized to receive Norditropin 0.034mg daily in main trial, extension trial period and safety extension trial period.

Subject analysis set title

Norditropin /somapacitan (0.16mg/kg/week) week 156-364

Subject analysis set type

Full analysis

Subject analysis set description

After completing the safety extension trial period (week 156), subjects who received Norditropin were allocated to open-labelled somapacitan 0.16 mg/kg/week for the 208-week (up till week 364) long-term safety extension period.

Subject analysis set title

Cohort II & Cohort III

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received somapacitan 0.16mg/kg/weekly subcutaneously from week 156 until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Subject analysis set title

Cohort I Norditropin/somapacitan

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received Norditropin 0.034 mg/kg subcutaneously once weekly in main trial period (26 weeks), extension trial period (26 weeks) and 104 week safety extension trial period. In long terms safety extension period all subjects who received Norditropin 0.034 mg/kg were allocated to open-labelled somapacitan 0.16 mg/kg/week for the 208-week long term safety extension period (up till week 364).

Subject analysis set title

Cohort I somapacitan pooled

Subject analysis set type

Full analysis

Subject analysis set description

Subjects were randomized (1:1:1) to receive somapacitan treatment (0.04/0.08/0.16 mg/kg) subcutaneously once-weekly during the 26-week main trial period and the 26-week extension trial period. After completing the main and extension trial periods (week 52), all subjects initially randomized to double-blinded somapacitan received open-labelled somapacitan 0.16 mg/kg/week treatment for the 104-week safety extension trial period. After completing the safety extension trial period (week 156), all subjects in cohort I were allocated to open-labelled somapacitan 0.16 mg/kg/week for the 208-week (up till week 364) long-term safety extension period.

Subject analysis sets values	Norditropin 0.034 mg/kg/day	somapacitan 0.04mg/kg/week	somapaciatn 0.08mg/kg/week	somapcitan 0.16mg/kg/week	Norditropin 0.034mg/kg/day 0-156 week Cohort I	Norditropin /somapacitan (0.16mg/kg/week) week 156-364	Cohort II & Cohort III	Cohort I Norditropin/somapacitan	Cohort I somapacitan pooled
Number of subjects	14	14	15	14	14	11	17	14	45
Age Categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)							8
Adolescents (12-17 years)							9
Adults (18-64 years)
From 65-84 years
85 years and over
Age Continuous
Units: years
arithmetic mean (standard deviation)	( )	( )	( )	( )	( )	( )	( )	( )	( )
Gender Categorical
Units: Subjects
Female							2
Male							15

End points

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Reporting group title

Cohort I Norditropin/somapacitan

Reporting group description

Subjects received Norditropin 0.034 miligram per kilogram (mg/kg) subcutaneously once weekly during (26 week) main trial period and (26 week) extension trial period.

Reporting group title

Cohort I somapacitan pooled

Reporting group description

Subjects were randomized (1:1:1) to receive somapacitan treatment (0.04/0.08/0.16 mg/kg/week) subcutaneously once-weekly during the (26 week) main trial period and (26 week) extension trial period.

Reporting group title

Cohort I Norditropin/somapacitan

Reporting group description

Subjects received Norditropin 0.034 miligram per kilogram (mg/kg) subcutaneously once weekly during (104 week) safety extension period.

Reporting group title

Cohort I somapacitan pooled

Reporting group description

Reporting group title

Cohort I Norditropin/somapacitan

Reporting group description

Subjects who received Norditropin until week 156 were given somapacitan 0.16 mg/kg subcutaneously once weekly for the 208-week long terms safety extension period (up till week 364)

Reporting group title

Cohort I somapacitan pooled

Reporting group description

Subjects received somapacitan 0.16 mg/kg subcutaneously once weekly for the 208-week long terms safety extension period (up till week 364)

Reporting group title

Cohort II somapacitan previously treated

Reporting group description

Reporting group title

Cohort III somapacitan treatment naive

Reporting group description

Reporting group title

Cohort III somapacitan previously treated

Reporting group description

Reporting group title

Cohort I Norditropin/somapacitan

Reporting group description

Subjects received somapacitan 0.16 mg/kg subcutaneously once weekly until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Reporting group title

Cohort I somapacitan pooled

Reporting group description

Subjects received somapacitan 0.16 mg/kg subcutaneously once weekly until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Subject analysis set title

Norditropin 0.034 mg/kg/day

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received Norditropin 0.034 mg/kg subcutaneously daily during 26 weeks main trial period.

Subject analysis set title

somapacitan 0.04mg/kg/week

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received somapacitan 0.04 mg/kg subcutaneously once weekly during 26 weeks main trial period.

Subject analysis set title

somapaciatn 0.08mg/kg/week

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received somapacitan 0.08 mg/kg subcutaneously once weekly during 26 weeks main trial period.

Subject analysis set title

somapcitan 0.16mg/kg/week

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received somapacitan 0.16 mg/kg subcutaneously once weekly during 26 weeks main trial period.

Subject analysis set title

Norditropin 0.034mg/kg/day 0-156 week Cohort I

Subject analysis set type

Full analysis

Subject analysis set description

Subjects were randomized to receive Norditropin 0.034mg daily in main trial, extension trial period and safety extension trial period.

Subject analysis set title

Norditropin /somapacitan (0.16mg/kg/week) week 156-364

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Cohort II & Cohort III

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Cohort I Norditropin/somapacitan

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Cohort I somapacitan pooled

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Cohort I: Height velocity (HV) (cm/year) during first 26 week of treatment, measured as standing height with stadiometer

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End point title

Cohort I: Height velocity (HV) (cm/year) during first 26 week of treatment, measured as standing height with stadiometer

End point description

Height velocity (HV) was derived from height measurements taken at baseline (week 0) and the week 26 as: HV = (height at 26 weeks visit- height at baseline) / (time from baseline to 26 weeks visit in years). Full analysis set (FAS) was used to analyse this endpoint. FAS is defined as all randomized subjects that received at least one dose of randomized treatment.

End point type

Primary

End point timeframe

At baseline and after 26 weeks

End point values	Norditropin 0.034 mg/kg/day	somapacitan 0.04mg/kg/week	somapaciatn 0.08mg/kg/week	somapcitan 0.16mg/kg/week
Number of subjects analysed	14	14	15	14
Units: Centimeter per year (Cm/year)
arithmetic mean (standard deviation)	11.35 ( 3.27 )	7.96 ( 2.04 )	10.92 ( 1.90 )	12.88 ( 3.46 )

Norditropin vs Somapacitan

Statistical analysis description

The primary analysis tested the estimated treatment difference in HV after 26 weeks of treatment between once-weekly Somapacitan 0.04 mg/kg and daily dosing of Norditropin (0.034 mg/kg). It was analysed using a mixed model for repeated measurements, with treatment, age group, sex, region and sex by age group interaction as factors and height at baseline as a covariate, all nested within week as a factor.

Comparison groups

Norditropin 0.034 mg/kg/day v somapacitan 0.04mg/kg/week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Estimated Treatment difference

Point estimate

-3.66

Confidence interval

level

95%

sides

2-sided

lower limit

-5.57

upper limit

-1.76

Norditropin vs Somapacitan

Statistical analysis description

The primary analysis tested the estimated treatment difference in HV after 26 weeks of treatment between once-weekly Somapacitan 0.16 mg/kg and daily dosing of Norditropin (0.034 mg/kg). It was analysed using a mixed model for repeated measurements, with treatment, age group, sex, region and sex by age group interaction as factors and height at baseline as a covariate, all nested within week as a factor.

Comparison groups

Norditropin 0.034 mg/kg/day v somapcitan 0.16mg/kg/week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Estimated treatment difference

Point estimate

1.67

Confidence interval

level

95%

sides

2-sided

lower limit

-0.22

upper limit

3.56

Norditropin vs Somapacitan

Statistical analysis description

The primary analysis tested the estimated treatment difference in HV after 26 weeks of treatment between once-weekly Somapacitan 0.08 mg/kg and daily dosing of Norditropin (0.034 mg/kg). It was analysed using a mixed model for repeated measurements, with treatment, age group, sex, region and sex by age group interaction as factors and height at baseline as a covariate, all nested within week as a factor.

Comparison groups

Norditropin 0.034 mg/kg/day v somapaciatn 0.08mg/kg/week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Estimated treatment difference

Point estimate

-0.55

Confidence interval

level

95%

sides

2-sided

lower limit

-2.41

upper limit

1.32

Primary: Cohort II and III: Incidence of adverse events, including injection site reactions in children with GHD.

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End point title

Cohort II and III: Incidence of adverse events, including injection site reactions in children with GHD. ^[1]

End point description

The primary endpoint was analysed by cohort using descriptive statistics. All participants of Cohort II and Cohort III were analysed for this endpoint. All participants defined as: all adverse events with an onset after the first administration of trial product and up until 14 days after last trial drug administration for withdrawn participants, and with an onset after the first administration of trial product and up until visit 32 (week 208) or 14 days after last trial drug administration, which ever comes first, for all participants are included in the analysis.

End point type

Primary

End point timeframe

During up to 208 weeks of treatment

Notes
[1] - 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: The primary endpoint investigated safety and was analysed using descriptive statistics, and thus no statistical analysis was performed.

End point values	Cohort II somapacitan previously treated	Cohort III somapacitan treatment naive	Cohort III somapacitan previously treated
Number of subjects analysed	1	4	12
Units: Events	42	12	55

No statistical analyses for this end point

Secondary: Cohort I: Change in Height standard deviation score (HSDS)

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End point title

Cohort I: Change in Height standard deviation score (HSDS)

End point description

Change in height standard deviation score is presented from baseline (week 0) to end of the main trial period week 26. The formula to calculate HSDS is: HSDS = ((Height / M)**L-1) / (L*S). L: The sex and age-specific power in the Box-Cox transformation, M: The sex and age-specific median, S: The sex and age-specific generalized coefficient of variation. The range for HSDS was -10 to +10. Negative scores indicated a height below the mean height for a child with the same age and gender, whereas positive scores indicated a height above the mean height for a child with the same age and gender. FAS was used to analyse this endpoint. (FAS) is defined as all randomised subjects that received at least one dose of randomised treatment.

End point type

Secondary

End point timeframe

From baseline to end of main trial period (week 26)

End point values	Norditropin 0.034 mg/kg/day	somapacitan 0.04mg/kg/week	somapaciatn 0.08mg/kg/week	somapcitan 0.16mg/kg/week
Number of subjects analysed	14	14	15	14
Units: Score on scale
arithmetic mean (standard deviation)	0.66 ( 0.37 )	0.31 ( 0.29 )	0.63 ( 0.29 )	0.88 ( 0.52 )

No statistical analyses for this end point

Secondary: Cohort I: Change in Height velocity standard deviation score (HVSDS)

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End point title

Cohort I: Change in Height velocity standard deviation score (HVSDS)

End point description

Change in height velocity standard deviation score is presented from baseline (week 0) to end of main trial period week 26. HVSDS was calculated using the formula: HVSDS = (height velocity - mean)/standard deviation (SD), where height velocity was the height velocity variable measured, mean and SD of height velocity by gender and age for the reference population. The range for HVSDS was -10 to +10. Negative scores indicated a height velocity below the mean height velocity for a child with the same age and gender, whereas positive scores indicated a height velocity above the mean height velocity for a child with the same age and gender. FAS was used to analyse this endpoint. (FAS) is defined as all randomised subjects that received at least one dose of randomised treatment.

End point type

Secondary

End point timeframe

From baseline to end of main trial period (week 26)

End point values	Norditropin 0.034 mg/kg/day	somapacitan 0.04mg/kg/week	somapaciatn 0.08mg/kg/week	somapcitan 0.16mg/kg/week
Number of subjects analysed	14	14	15	14
Units: Score on scale
arithmetic mean (standard deviation)	9.02 ( 5.03 )	4.93 ( 3.25 )	7.27 ( 3.76 )	10.01 ( 4.67 )

No statistical analyses for this end point

Secondary: Cohort I: Incidence of adverse events, including injection site reactions

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End point title

Cohort I: Incidence of adverse events, including injection site reactions

End point description

Adverse events with an onset after the first administration of trial product and up until 14 days after last trial drug administration for withdrawn participants, and with an onset after the first administration of trial product and up until visit 32 (week 364) or 14 days after last trial drug administration, which ever comes first, for all other participants, are analysed. Safety analysis set (SAS) was used to analyse this endpoint. SAS is defined as all randomized subjects that received at least one dose of randomized treatment.

End point type

Secondary

End point timeframe

Up to 364 weeks of treatment

End point values	Norditropin 0.034mg/kg/day 0-156 week Cohort I	Norditropin /somapacitan (0.16mg/kg/week) week 156-364	Cohort I somapacitan pooled
Number of subjects analysed	14	11	45
Units: events	95	46	582

No statistical analyses for this end point

Secondary: Cohort I: Occurrence of anti-NNC0195-0092 and anti-hGH antibodies

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End point title

Cohort I: Occurrence of anti-NNC0195-0092 and anti-hGH antibodies

End point description

Subjects who developed anti-NNC0195-0092 and anti-hGH antibodies are reported in this endpoint. Safety analysis set (SAS) was used to analyse this endpoint. SAS is defined as all randomized subjects that received at least one dose of randomized treatment.

End point type

Secondary

End point timeframe

Up to 364 weeks of treatment

End point values	Cohort I Norditropin/somapacitan	Cohort I somapacitan pooled
Number of subjects analysed	14	45
Units: Participants
Anti-NNC0195-0092 antibody	0	12
Anti-hGH antibody	1	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Week 0 to week 442

Adverse event reporting additional description

Cohort I: SAS All presented AEs are TEAEs (treatment emergent adverse events). Cohort II & III: All participants

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Cohort I Norditropin (0.034mg/kg/day) week 0-156

Reporting group description

Subjects received Norditropin 0.034 mg/kg subcutaneously daily in main trial, extension trial period and safety extension trial period.

Reporting group title

Cohort I Norditropin (0.034mg/somapacitan 0.16mg) week 156-364

Reporting group description

After completing the safety extension trial period (week 156), subjects who received Norditropin were allocated to open-labelled Somapacitan 0.16 mg/kg subcutaneously once weekly for the 208-week (up till week 364) long-term safety extension period.

Reporting group title

Cohort I somapacitan (0.04/0.08/0.16mg/kg/week) pooled

Reporting group description

Subjects were randomized (1:1:1) to receive Somapacitan treatment (0.04/0.08/0.16 mg/kg) subcutaneously once-weekly during the 26-week main trial period and the 26-week extension trial period. After completing the main and extension trial periods (week 52), all subjects initially randomized to double-blinded Somapacitan received open-labelled Somapacitan 0.16 mg/kg/week treatment for the 104-week safety extension trial period. After completing the safety extension trial period (week 156), all subjects in cohort I were allocated to open-labelled somapacitan 0.16 mg/kg/week for the 208-week (up till week 364) long-term safety extension period. In extension after week 364 period subjects received somapacitan 0.16 mg/kg subcutaneously once weekly until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Reporting group title

Cohort II somapacitan(0.16mg/kg/week) previously treated

Reporting group description

Reporting group title

Cohort III somapacitan(0.16mg/kg/week) treatment naive

Reporting group description

Reporting group title

Cohort III somapacitan(0.16mg/kg/week) previously treated

Reporting group description

Reporting group title

Cohort I Norditropin (0.034mg/somapacitan 0.16mg) week > 364

Reporting group description

Subjects received somapacitan 0.16 mg/kg subcutaneously once weekly until somapacitan was available for prescription for children with GHD in their country or until August 2024, at the latest.

Serious adverse events	Cohort I Norditropin (0.034mg/kg/day) week 0-156	Cohort I Norditropin (0.034mg/somapacitan 0.16mg) week 156-364	Cohort I somapacitan (0.04/0.08/0.16mg/kg/week) pooled	Cohort II somapacitan(0.16mg/kg/week) previously treated	Cohort III somapacitan(0.16mg/kg/week) treatment naive	Cohort III somapacitan(0.16mg/kg/week) previously treated	Cohort I Norditropin (0.034mg/somapacitan 0.16mg) week > 364
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 14 (14.29%)	0 / 11 (0.00%)	7 / 45 (15.56%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Surgical and medical procedures
Adenoidectomy
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Seizure
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
General disorders and administration site conditions
Generalised oedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Anaphylactic shock
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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	0 / 0	0 / 0
Renal and urinary disorders
Nephrotic syndrome
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypopituitarism
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Epiphysiolysis
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Norovirus infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0

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

Non-serious adverse events	Cohort I Norditropin (0.034mg/kg/day) week 0-156	Cohort I Norditropin (0.034mg/somapacitan 0.16mg) week 156-364	Cohort I somapacitan (0.04/0.08/0.16mg/kg/week) pooled	Cohort II somapacitan(0.16mg/kg/week) previously treated	Cohort III somapacitan(0.16mg/kg/week) treatment naive	Cohort III somapacitan(0.16mg/kg/week) previously treated	Cohort I Norditropin (0.034mg/somapacitan 0.16mg) week > 364
Total subjects affected by non serious adverse events
subjects affected / exposed	14 / 14 (100.00%)	10 / 11 (90.91%)	40 / 45 (88.89%)	1 / 1 (100.00%)	2 / 4 (50.00%)	9 / 12 (75.00%)	2 / 5 (40.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	4 / 45 (8.89%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	6	0	0	0	0
Surgical and medical procedures
Cranial operation
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	0	1	0
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Pyrexia
subjects affected / exposed	2 / 14 (14.29%)	1 / 11 (9.09%)	18 / 45 (40.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	5	6	30	5	0	1	0
Fatigue
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	2 / 4 (50.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Injection site reaction
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	1	0	0	0	0
Malaise
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	1	0	0	0	0
Temperature intolerance
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Food allergy
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	1 / 45 (2.22%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	1	1	0	0	0
Seasonal allergy
subjects affected / exposed	1 / 14 (7.14%)	1 / 11 (9.09%)	3 / 45 (6.67%)	1 / 1 (100.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	2	3	5	1	0	1	0
Social circumstances
Educational problem
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Social problem
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	2 / 45 (4.44%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	3	1	0	0	0
Cough
subjects affected / exposed	2 / 14 (14.29%)	1 / 11 (9.09%)	4 / 45 (8.89%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	1	5	0	1	0	0
Rhinitis allergic
subjects affected / exposed	3 / 14 (21.43%)	0 / 11 (0.00%)	6 / 45 (13.33%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	0	12	0	0	0	0
Adenoidal hypertrophy
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Epistaxis
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	3	0	1	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	4	0	0	0	0
Rhinorrhoea
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Psychiatric disorders
Attention deficit hyperactivity disorder
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	3	0	0	1	0
Autism spectrum disorder
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Drug abuse
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Generalised anxiety disorder
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Blood glucose abnormal
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	1	0	0	0	0
Platelet count increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	4 / 45 (8.89%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	6	0	0	0	0
Head injury
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	3	0	0	0	0
Arthropod bite
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	3	0	0	0	0
Arthropod sting
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	3	0	0	0	0
Hand fracture
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	3	0	0	0	0
Skin laceration
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	3	0	0	0	0
Cardiac disorders
Defect conduction intraventricular
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Ventricular extrasystoles
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Nervous system disorders
Autonomic nervous system imbalance
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Disturbance in attention
subjects affected / exposed	1 / 14 (7.14%)	1 / 11 (9.09%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	0	0	0	0	0
Febrile convulsion
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Headache
subjects affected / exposed	2 / 14 (14.29%)	0 / 11 (0.00%)	5 / 45 (11.11%)	0 / 1 (0.00%)	1 / 4 (25.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)
occurrences all number	2	0	9	0	1	3	0
Nystagmus
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Sensory processing disorder
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Speech disorder developmental
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Speech disorder
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	3	0	0	0	0
Microcytosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Monocytosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Eye disorders
Anisometropia
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Optic nerve cupping
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Strabismus
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Conjunctivitis allergic
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	4 / 45 (8.89%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	6	0	0	0	0
Visual impairment
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Swelling of eyelid
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	7 / 45 (15.56%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	13	0	0	0	0
Diarrhoea
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	4 / 45 (8.89%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	10	2	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Abdominal pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	5 / 45 (11.11%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	6	0	0	0	0
Vomiting
subjects affected / exposed	1 / 14 (7.14%)	2 / 11 (18.18%)	8 / 45 (17.78%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	4	2	9	0	1	0	0
Nausea
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	4 / 45 (8.89%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	5	0	1	0	0
Stomatitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	4 / 45 (8.89%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	24	0	0	0	0
Hepatobiliary disorders
Gallbladder disorder
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Non-alcoholic fatty liver
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	3 / 45 (6.67%)	1 / 1 (100.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	1	0	3	1	0	3	0
Dermatitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	2 / 45 (4.44%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	2	0	0	0	0
Eczema asteatotic
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Eczema
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	5 / 45 (11.11%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	0	6	0	0	0	1
Dermatosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Dermatitis atopic
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	0 / 45 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	1	0	1	0	0	1
Haemorrhage subcutaneous
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Hair colour changes
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Rash
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	4	0	0	0	0
Seborrhoea
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 14 (7.14%)	1 / 11 (9.09%)	6 / 45 (13.33%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	1	1	7	0	0	1	0
Groin pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Pain in extremity
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	4 / 45 (8.89%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	1	0	6	0	0	1	0
Foot deformity
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Growing pains
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	4	0	0	0	0
Neck pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Infections and infestations
Gastroenteritis
subjects affected / exposed	2 / 14 (14.29%)	1 / 11 (9.09%)	8 / 45 (17.78%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	1	11	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	4 / 45 (8.89%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	8	0	0	1	0
Ear infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	2	0
Nasopharyngitis
subjects affected / exposed	3 / 14 (21.43%)	2 / 11 (18.18%)	9 / 45 (20.00%)	1 / 1 (100.00%)	1 / 4 (25.00%)	3 / 12 (25.00%)	0 / 5 (0.00%)
occurrences all number	12	4	67	12	1	8	0
Otitis media
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	7 / 45 (15.56%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	12	7	0	0	0
Mumps
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Influenza
subjects affected / exposed	3 / 14 (21.43%)	1 / 11 (9.09%)	11 / 45 (24.44%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	4	1	18	1	0	0	0
Pneumonia
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	3	0	0	0	0
Rhinitis
subjects affected / exposed	3 / 14 (21.43%)	2 / 11 (18.18%)	2 / 45 (4.44%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	2	3	0	0	0	0
Respiratory tract infection viral
subjects affected / exposed	1 / 14 (7.14%)	2 / 11 (18.18%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	2	2	0	0	0	0
Respiratory tract infection
subjects affected / exposed	2 / 14 (14.29%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	0	7	0	0	0	0
Varicella
subjects affected / exposed	1 / 14 (7.14%)	1 / 11 (9.09%)	2 / 45 (4.44%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	2	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	2 / 14 (14.29%)	0 / 11 (0.00%)	5 / 45 (11.11%)	1 / 1 (100.00%)	0 / 4 (0.00%)	3 / 12 (25.00%)	1 / 5 (20.00%)
occurrences all number	3	0	10	4	0	5	1
Tonsillitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	6 / 45 (13.33%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	6	0	0	0	0
Viral infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	4	0	0	0	0
Bronchitis
subjects affected / exposed	2 / 14 (14.29%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	0	4	0	0	0	0
COVID-19
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	14 / 45 (31.11%)	1 / 1 (100.00%)	1 / 4 (25.00%)	3 / 12 (25.00%)	0 / 5 (0.00%)
occurrences all number	0	0	17	1	1	4	0
Conjunctivitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	2 / 45 (4.44%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	2	1	0	0	0
Helicobacter infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Hordeolum
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	1	1	0	0	1	0
Hand-foot-and-mouth disease
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Impetigo
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	3	0	0	0	0
Otitis media acute
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	2 / 45 (4.44%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	3	1	0	0	0
Oral herpes
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Paronychia
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	3	0	0	0	0
Pharyngitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	3 / 45 (6.67%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	7	0	0	4	0
Scarlet fever
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Pyoderma
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Pharyngitis streptococcal
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	0	4	0	0	1	0
Streptococcal infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	1 / 45 (2.22%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	1	0	0	0	0
Tooth abscess
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Impaired fasting glucose
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 45 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Vitamin D deficiency
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)	2 / 45 (4.44%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)
occurrences all number	0	1	2	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

29 Sep 2016

The amendment was implemented to add a 104-week safety extension trial period to the original trial in order to evaluate long-term safety of somapacitan in paediatric patients with GHD. Additional key changes: - With the addition of Japan as a participating country, it was added that randomisation was stratified by region (Japan and rest-of-the-world) 1)Text on directions for pregnancy in female subjects updated. 2)HV was added as a secondary efficacy endpoint. 3)Serum somapacitan concentrations and changes during the trial were moved from a secondary safety endpoint to a secondary efficacy endpoint. 4)The patient information informed consents (PI-ICs) were updated to be aligned with the changes described above and in Appendix 9.1.1.

05 Jan 2018

The amendment was prepared to include a description of how subjects that discontinue treatment was to be followed in the trial. After introducing a 2-year safety extension period with amendment no 5 it was necessary to describe which visits and assessments subjects that discontinue trial product should perform.

12 Feb 2019

The amendment was prepared to introduce a 208-week long-term safety extension trial period in order to evaluate long-term safety of somapacitan in paediatric patients with GHD. The children receiving daily doses of Norditropin FlexPro were to be switched to weekly doses of somapacitan at week 156. Additional key changes: 1) It was added that adult height will be collected on a subset of subjects in the long-term safety extension period. 2) Clarification of endpoints for the 26-week main trial period and the 26 week extension trial period. 3) Height SDS and HV SDS, insulin-like growth factor-I (IGF-I) SDS and insulin-like growth factor binding protein-3 (IGFBP-3) SDS were added as secondary efficacy endpoints for evaluation after 52 weeks. 4) The former secondary supportive safety endpoint, bone age (X-Ray of left hand), was moved to the efficacy section. 5) A number of supportive safety endpoints were removed, including evaluation of technical complaints and change from baseline in physical signs, vital signs and laboratory parameters, as they are monitored on an ongoing basis as part of standard pharmacovigilance practice. 6) A number of efficacy and safety analyses, not directly linked to the endpoints, were specified. 7) The PI-ICs were updated to be aligned with the changes described above.

13 Dec 2019

The amendment was prepared to introduce two additional age groups; cohort II (less than (<) 2 years and 26 weeks) and cohort III (girls: more than (>) 9 years and less than equal to (≤) 17 years; boys: >10 years and ≤17 years), of children with GHD to the 208-week long-term safety extension period of the trial. The aim of adding the two age groups, cohorts II and III, was to enrol children with GHD to whom treatment may be relevant based on a request from the US Food and Drug Administration (FDA). Additional key changes in this context: 1) Updated descriptions of the trial design, treatment and rationale for the trial design as well as updated flowcharts to reflect the addition of cohorts II and III. 2) Objectives and endpoints were added for cohort II and III 3) Inclusion and exclusion criteria were added for cohorts II and III 4) Treatment discontinuation criteria were added for cohorts III 5) Updates on visit procedures and timing of visits to reflect the addition of cohorts II and III 6) Addition of PI-ICs for cohorts II and III including consent for child becoming of legal age.

13 Apr 2021

The amendment was prepared to clarify that inclusion criterion 21 for cohort III (Bone age (X-ray of left hand and wrist, central reviewed according to Greulich & Pyle atlas) less than chronological age at screening) is only applicable for growth hormone (GH) treatment naïve subjects, as children receiving GH treatment generally have a more advanced bone age than GH treatment naïve children.

31 Oct 2022

The amendment was prepared to specify that the trial will be concluded for cohort II and III subjects latest August 2024 (expected last end-of-treatment visit for cohort I) and to describe which visits and assessments should be performed when treatment is discontinued.

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

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cohort I: Height velocity (HV) (cm/year) during first 26 week of treatment, measured as standing height with stadiometer

Primary: Cohort I: Height velocity (HV) (cm/year) during first 26 week of treatment, measured as standing height with stadiometer

Primary: Cohort II and III: Incidence of adverse events, including injection site reactions in children with GHD.

Primary: Cohort II and III: Incidence of adverse events, including injection site reactions in children with GHD.

Secondary: Cohort I: Change in Height standard deviation score (HSDS)

Secondary: Cohort I: Change in Height standard deviation score (HSDS)

Secondary: Cohort I: Change in Height velocity standard deviation score (HVSDS)

Secondary: Cohort I: Change in Height velocity standard deviation score (HVSDS)

Secondary: Cohort I: Incidence of adverse events, including injection site reactions

Secondary: Cohort I: Incidence of adverse events, including injection site reactions

Secondary: Cohort I: Occurrence of anti-NNC0195-0092 and anti-hGH antibodies

Secondary: Cohort I: Occurrence of anti-NNC0195-0092 and anti-hGH antibodies

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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