Download PDF

Clinical Trial Results:
An Open-label, Sequential, Ascending, Repeated Dose-finding Study of Sarilumab, Administered with Subcutaneous (SC) Injection, in Children and Adolescents, Aged 2 to 17 Years, with Polyarticular-course Juvenile Idiopathic Arthritis (pcJIA) Followed by an Extension Phase

Summary
EudraCT number	2015-003999-79
Trial protocol	GB IT CZ ES Outside EU/EEA EE FI NL PL DE FR
Global end of trial date	28 Dec 2023

Results information
Results version number	v1
This version publication date	10 Jul 2024
First version publication date	10 Jul 2024
Other versions	v2

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

DRI13925

ISRCTN number

US NCT number

NCT02776735

WHO universal trial number (UTN)

U1111-1177-3487

Sponsor organisation name

Sanofi-Aventis Recherche & Développement

Sponsor organisation address

82 Avenue Raspail, Gentilly, France, 94250

Public contact

Trial Transparency Team, Sanofi-Aventis Recherche & Developpement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi-Aventis Recherche & Developpement, Contact-US@sanofi.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001045-PIP01-10

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

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

Analysis stage

Final

Date of interim/final analysis

02 Feb 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Dec 2023

Was the trial ended prematurely?

Main objective of the trial

To describe the Pharmacokinetic (PK) profile of sarilumab in participants aged 2 to 17 years with polyarticular-course Juvenile Idiopathic Arthritis (pcJIA) in order to identify the dose and regimen for adequate treatment of this population.

Protection of trial subjects

The study was conducted by investigators experienced in the treatment of pediatric patients. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parents(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Oct 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 9

Country: Number of subjects enrolled

Canada: 1

Country: Number of subjects enrolled

Chile: 2

Country: Number of subjects enrolled

Czechia: 2

Country: Number of subjects enrolled

Finland: 1

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Germany: 12

Country: Number of subjects enrolled

Italy: 1

Country: Number of subjects enrolled

Mexico: 8

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Poland: 15

Country: Number of subjects enrolled

Russian Federation: 25

Country: Number of subjects enrolled

Spain: 16

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

United States: 2

Worldwide total number of subjects

102

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

Top of page

Recruitment details

The study was conducted at 29 centers in 15 countries. A total of 118 participants were screened from 06 September 2016 and 20 December 2021, of which 16 were screen failures. The main reasons for screen failure were based on criteria for exclusion from the study.

Screening details

A total of 102 participants were enrolled in the study. The dose was capped at 150 milligram (mg) and 200 mg for Cohorts 1 and 3 and Cohort 2, respectively. Cohort 2 was selected dose treatment regimen and participants enrolled directly in selected dose (portions 2 and 3) didn't have upper body weight limit.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1: >= 30 kg and <= 60 kg

Arm description

Participants with body weight >= 30 kilograms (kg) and <= 60 kg received sarilumab 2 mg/kg subcutaneous (SC) injection once every other week (q2w) for 12 weeks in core treatment phase (portion 1). Eligible participants continued to receive 2 mg/kg SC injection q2w until the selected dose was found and then switched to selected dose of 3 mg/kg SC injection q2w in extension phase (portion 2: up to 144 weeks and portion 3: up to 84 weeks).

Arm type

Experimental

Investigational medicinal product name

Sarilumab

Investigational medicinal product code

Other name

Kevzara®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sarilumab 2 mg/kg q2w was administered SC in 1 of the 4 quadrants of the abdomen or thigh when self injected or also in the upper arm (lateral side) if administered by a professional or a nonprofessional caregiver.

Cohort 1: < 30 kg and >= 10 kg

Arm description

Participants with body weight < 30 kg and >= 10 kg received sarilumab 2.5 mg/kg SC injection q2w for 12 weeks in core treatment phase (portion 1). Eligible participants continued to receive 2.5 mg/kg SC injection q2w until the selected dose was found and then switched to selected dose of 4 mg/kg SC injection q2w in extension phase (portion 2: up to 144 weeks and portion 3: up to 84 weeks).

Arm type

Experimental

Investigational medicinal product name

Sarilumab

Investigational medicinal product code

Other name

Kevzara®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sarilumab 2.5 mg/kg q2w was administered SC in 1 of the 4 quadrants of the abdomen or thigh when self injected or also in the upper arm (lateral side) if administered by a professional or a nonprofessional caregiver.

Cohort 2: >= 30 kg and <= 60 kg

Arm description

Participants with body weight >= 30 kg and <= 60 kg received sarilumab 3 mg/kg SC injection q2w for 12 weeks in core treatment phase (portion 1). Eligible participants continued to receive 3 mg/kg SC injection q2w in extension phase (portion 2: up to 144 weeks and portion 3: up to 84 weeks).

Arm type

Experimental

Investigational medicinal product name

Sarilumab

Investigational medicinal product code

Other name

Kevzara®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sarilumab 3 mg/kg q2w was administered SC in 1 of the 4 quadrants of the abdomen or thigh when self injected or also in the upper arm (lateral side) if administered by a professional or a nonprofessional caregiver.

Cohort 2: < 30 kg and >= 10 kg

Arm description

Participants with body weight < 30 kg and >= 10 kg received sarilumab 4 mg/kg SC injection q2w for 12 weeks in core treatment phase (portion 1). Eligible participants continued to receive 4 mg/kg SC injection q2w in extension phase (portion 2: up to 144 weeks and portion 3: up to 84 weeks).

Arm type

Experimental

Investigational medicinal product name

Sarilumab

Investigational medicinal product code

Other name

Kevzara®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sarilumab 4 mg/kg q2w was administered SC in 1 of the 4 quadrants of the abdomen or thigh when self injected or also in the upper arm (lateral side) if administered by a professional or a nonprofessional caregiver.

Cohort 3: >= 30 kg and <= 60 kg

Arm description

Participants with body weight >= 30 kg and <= 60 kg received sarilumab 2 mg/kg SC injection once every week (qw) for 12 weeks in core treatment phase (portion 1). Eligible participants continued to receive 2 mg/kg SC injection qw until the selected dose was found and then switched to selected dose of 3 mg/kg SC injection qw in extension phase (portion 2: up to 144 weeks and portion 3: up to 84 weeks).

Arm type

Experimental

Investigational medicinal product name

Sarilumab

Investigational medicinal product code

Other name

Kevzara®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sarilumab 2 mg/kg qw was administered SC in 1 of the 4 quadrants of the abdomen or thigh when self injected or also in the upper arm (lateral side) if administered by a professional or a nonprofessional caregiver.

Cohort 3: < 30 kg and >= 10 kg

Arm description

Participants with body weight < 30 kg and >= 10 kg received sarilumab 2.5 mg/kg SC injection qw for 12 weeks in core treatment phase (portion 1). Eligible participants continued to receive 2.5 mg/kg SC injection qw until the selected dose was found and then switched to selected dose of 4 mg/kg SC injection qw in extension phase (portion 2: up to 144 weeks and portion 3: up to 84 weeks).

Arm type

Experimental

Investigational medicinal product name

Sarilumab

Investigational medicinal product code

Other name

Kevzara®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sarilumab 2.5 mg/kg qw was administered SC in 1 of the 4 quadrants of the abdomen or thigh when self injected or also in the upper arm (lateral side) if administered by a professional or a nonprofessional caregiver.

Number of subjects in period 1 ^[1]	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Started	7	6	42	31	6	9
Completed	6	6	38	27	6	7
Not completed	1	0	4	4	0	2
Consent withdrawn by subject	1	-	-	-	-	1
Adverse event, non-fatal	-	-	-	1	-	1
Unspecified	-	-	2	-	-	-
Lost to follow-up	-	-	-	1	-	-
Withdrawal by parent/guardian	-	-	2	2	-	-

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: Only treated participants included.

Baseline characteristics

Top of page

Reporting group title

Cohort 1: >= 30 kg and <= 60 kg

Reporting group description

Reporting group title

Cohort 1: < 30 kg and >= 10 kg

Reporting group description

Reporting group title

Cohort 2: >= 30 kg and <= 60 kg

Reporting group description

Reporting group title

Cohort 2: < 30 kg and >= 10 kg

Reporting group description

Reporting group title

Cohort 3: >= 30 kg and <= 60 kg

Reporting group description

Reporting group title

Cohort 3: < 30 kg and >= 10 kg

Reporting group description

Reporting group values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg	Total
Number of subjects	7	6	42	31	6	9	101
Age categorical
Units:
Age Continuous
Units: years
arithmetic mean (standard deviation)	12.3 ( 3.3 )	6.5 ( 3.2 )	12.6 ( 3.0 )	5.4 ( 3.1 )	13.7 ( 3.0 )	4.8 ( 2.4 )	-
Sex: Female, Male
Units: participants
Female	5	5	35	23	3	6	77
Male	2	1	7	8	3	3	24
Race
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	0	0	1	0	0	0	1
Black or African American	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
White	6	3	39	28	4	8	88
Not Reported	0	1	2	3	0	1	7
Unknown	1	2	0	0	2	0	5

End points

Top of page

Reporting group title

Cohort 1: >= 30 kg and <= 60 kg

Reporting group description

Reporting group title

Cohort 1: < 30 kg and >= 10 kg

Reporting group description

Reporting group title

Cohort 2: >= 30 kg and <= 60 kg

Reporting group description

Reporting group title

Cohort 2: < 30 kg and >= 10 kg

Reporting group description

Reporting group title

Cohort 3: >= 30 kg and <= 60 kg

Reporting group description

Reporting group title

Cohort 3: < 30 kg and >= 10 kg

Reporting group description

Primary: Maximum Serum Concentration (Cmax) at Steady State of Sarilumab

Top of page

End point title

Maximum Serum Concentration (Cmax) at Steady State of Sarilumab ^[1]

End point description

The Cmax was defined as maximum serum concentration. The PK analysis set included all participants in the safety population with at least 1 post-dose, non-missing serum concentration value. Only participants with data collected are reported.

End point type

Primary

End point timeframe

Pre-dose on Days 1, 3, 5, 8, 12 and Weeks 2, 4, 8 and 12

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: As the endpoint is descriptive in nature, no statistical analysis is provided.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	39	24	5	5
Units: milligram per liter (mg/L)
arithmetic mean (standard deviation)	11.1 ( 4.82 )	14.0 ( 2.97 )	27.1 ( 11.6 )	40.4 ( 7.77 )	37.6 ( 8.52 )	28.9 ( 5.32 )

No statistical analyses for this end point

Primary: Area Under the Serum Concentration Versus Time Curve Using the Trapezoidal Method During a Dose Interval (AUC0-t) at Steady State of Sarilumab

Top of page

End point title

Area Under the Serum Concentration Versus Time Curve Using the Trapezoidal Method During a Dose Interval (AUC0-t) at Steady State of Sarilumab ^[2]

End point description

The AUC0-t was defined as area under the concentration in serum versus time curve calculated using the trapezoidal method during a dose interval (tau). The PK analysis set included all participants in the safety population with at least 1 post-dose, non-missing serum concentration value. Only participants with data collected are reported.

End point type

Primary

End point timeframe

Pre-dose on Days 1, 3, 5, 8, 12 and Weeks 2, 4, 8 and 12

Notes
[2] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	39	24	5	5
Units: day*mg/L
arithmetic mean (standard deviation)	90.7 ( 30.8 )	110 ( 40.9 )	276 ( 121 )	395 ( 101 )	235 ( 60.9 )	176 ( 32.4 )

No statistical analyses for this end point

Primary: Concentration Before Treatment Administration During Repeated Dosing (Ctrough) at Steady State of Sarilumab

Top of page

End point title

Concentration Before Treatment Administration During Repeated Dosing (Ctrough) at Steady State of Sarilumab ^[3]

End point description

The Ctrough was defined as concentration observed before treatment administration during repeated dosing from baseline to Week 12. The PK analysis set included all participants in the safety population with at least 1 post-dose, non-missing serum concentration value. Only participants with data collected are reported.

End point type

Primary

End point timeframe

Pre-dose on Days 1, 3, 5, 8, 12 and Weeks 2, 4, 8 and 12

Notes
[3] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	39	24	5	5
Units: mg/L
arithmetic mean (standard deviation)	1.36 ( 0.872 )	1.39 ( 1.44 )	9.57 ( 5.84 )	14.4 ( 9.81 )	28.0 ( 9.06 )	21.6 ( 5.16 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Change From Baseline in High-Sensitivity C-reactive Protein (hs-CRP) at Week 12

Top of page

End point title

Cohorts 1 and 3: Change From Baseline in High-Sensitivity C-reactive Protein (hs-CRP) at Week 12 ^[4]

End point description

Serum concentrations of hs-CRP was determined to assess the Pharmacodynamic (PD) effects of sarilumab. All treated population included participants who signed informed consent and received at least 1 dose of the study treatment. Only participants analyzed at baseline and Week 12 are reported.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 12

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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	6	6	9
Units: mg/L
arithmetic mean (standard deviation)	-1.00 ( 2.53 )	-0.52 ( 3.64 )	-5.71 ( 8.90 )	-6.83 ( 11.74 )

No statistical analyses for this end point

Secondary: Cohort 2: Change From Baseline in High-Sensitivity C-reactive Protein at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Change From Baseline in High-Sensitivity C-reactive Protein at Weeks 12, 24, 48, 96, and 156 ^[5]

End point description

Serum concentrations of hs-CRP was determined to assess the PD effects of sarilumab. All treated population included participants who signed informed consent and received at least 1 dose of the study treatment. Here, n= number of participants analyzed at specific timepoints.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156

Notes
[5] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	40	29
Units: mg/L
arithmetic mean (standard deviation)
Week 12 (n= 40,29)	-3.54 ( 33.57 )	-20.66 ( 48.35 )
Week 24 (n= 37,29)	-8.54 ( 19.17 )	-11.72 ( 23.54 )
Week 48 (n= 38,27)	-9.93 ( 21.60 )	-12.57 ( 24.23 )
Week 96 (n= 36,23)	-9.39 ( 21.65 )	-13.88 ( 25.96 )
Week 156 (n= 16,16)	-5.10 ( 14.68 )	-12.30 ( 26.69 )

No statistical analyses for this end point

Secondary: Change From Baseline in Interleukin-6 (IL-6) at Week 12

Top of page

End point title

Change From Baseline in Interleukin-6 (IL-6) at Week 12

End point description

Serum concentrations of IL-6 was determined to assess the PD effects of sarilumab. All treated population included participants who signed informed consent and received at least 1 dose of the study treatment. Only participants with data collected at Baseline and Week 12 are reported.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 12

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	4	4	30	20	6	5
Units: nanogram (ng)/L
arithmetic mean (standard deviation)	1.27 ( 9.79 )	13.65 ( 18.20 )	43.71 ( 113.42 )	11.36 ( 35.81 )	66.21 ( 86.21 )	9.20 ( 26.50 )

No statistical analyses for this end point

Secondary: Change From Baseline in Total Soluble Interleukin-6 Receptor (sIL-6R) at Week 12

Top of page

End point title

Change From Baseline in Total Soluble Interleukin-6 Receptor (sIL-6R) at Week 12

End point description

Serum concentrations of sIL-6R was determined to assess the PD effects of sarilumab. All treated population included participants who signed informed consent and received at least 1 dose of the study treatment. Only participants with data collected at Baseline and Week 12 are reported.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 12

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	3	3	33	28	6	6
Units: ng/mL
arithmetic mean (standard deviation)	40.09 ( 49.75 )	101.50 ( 129.59 )	316.77 ( 129.29 )	388.33 ( 185.82 )	535.76 ( 98.12 )	582.95 ( 149.52 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology (JIA ACR) 30 Response at Week 12

Top of page

End point title

Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology (JIA ACR) 30 Response at Week 12 ^[6]

End point description

JIA ACR30 response was defined as a participant with at least 3 out of the 6 JIA core set variables with >= 30% improvement from baseline with no more than 1 of the remaining variables worsened by >= 30%. The efficacy analysis set included all participants who received at least 1 dose of sarilumab.

End point type

Secondary

End point timeframe

Week 12

Notes
[6] - 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	6	5
Units: percentage of participants with response
number (not applicable)	100	100	100	100

No statistical analyses for this end point

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 30 Response at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 30 Response at Weeks 12, 24, 48, 96, and 156 ^[7]

End point description

End point type

Secondary

End point timeframe

Weeks 12, 24, 48, 96, and 156

Notes
[7] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	39	29
Units: percentage of participants with response
number (not applicable)
Week 12 (n= 39,29)	100	100
Week 24 (n= 39,27)	100	100
Week 48 (n= 38,26)	100	100
Week 96 (n= 36,24)	97.2	100
Week 156 (n= 17,16)	94.1	100

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 50 Response at Week 12

Top of page

End point title

Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 50 Response at Week 12 ^[8]

End point description

JIA ACR50 response was defined as a participant with at least 3 out of the 6 JIA core set variables with >= 50% improvement from baseline with no more than 1 of the remaining variables worsened by >= 30%. The efficacy analysis set included all participants who received at least 1 dose of sarilumab.

End point type

Secondary

End point timeframe

Week 12

Notes
[8] - 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	6	5
Units: percentage of participants with response
number (not applicable)	80.0	100	100	100

No statistical analyses for this end point

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 50 Response at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 50 Response at Weeks 12, 24, 48, 96, and 156 ^[9]

End point description

End point type

Secondary

End point timeframe

Weeks 12, 24, 48, 96, and 156

Notes
[9] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	39	29
Units: percentage of participants with response
number (not applicable)
Week 12 (n= 39,29)	94.9	96.6
Week 24 (n= 39,27)	100	100
Week 48 (n= 38,26)	100	100
Week 96 (n= 36,24)	97.2	100
Week 156 (n= 17,16)	94.1	100

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 70 Response at Week 12

Top of page

End point title

Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 70 Response at Week 12 ^[10]

End point description

JIA ACR70 response was defined as a participant with at least 3 out of the 6 JIA core set variables with >= 70% improvement from baseline with no more than 1 of the remaining variables worsened by >= 30%. The efficacy analysis set included all participants who received at least 1 dose of sarilumab.

End point type

Secondary

End point timeframe

Week 12

Notes
[10] - 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	6	5
Units: percentage of participants with response
number (not applicable)	60.0	40.0	100	100

No statistical analyses for this end point

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 70 Response at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 70 Response at Weeks 12, 24, 48, 96, and 156 ^[11]

End point description

End point type

Secondary

End point timeframe

Weeks 12, 24, 48, 96, and 156

Notes
[11] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	39	29
Units: percentage of participants with response
number (not applicable)
Week 12 (n= 39,29)	74.4	89.7
Week 24 (n= 39,27)	87.2	96.3
Week 48 (n= 38,26)	89.5	100
Week 96 (n= 36,24)	97.2	100
Week 156 (n= 17,16)	94.1	100

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 90 Response at Week 12

Top of page

End point title

Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 90 Response at Week 12 ^[12]

End point description

JIA ACR90 response was defined as a participant with at least 3 out of the 6 JIA core set variables with >= 90% improvement from baseline with no more than 1 of the remaining variables worsened by >= 30%. The efficacy analysis set included all participants who received at least 1 dose of sarilumab.

End point type

Secondary

End point timeframe

Week 12

Notes
[12] - 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	6	5
Units: percentage of participants with response
number (not applicable)	60.0	20.0	66.7	60.0

No statistical analyses for this end point

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 90 Response at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 90 Response at Weeks 12, 24, 48, 96, and 156 ^[13]

End point description

End point type

Secondary

End point timeframe

Weeks 12, 24, 48, 96, and 156

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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	39	29
Units: percentage of participants with response
number (not applicable)
Week 12 (n= 39,29)	43.6	48.3
Week 24 (n= 39,27)	64.1	74.1
Week 48 (n= 38,26)	68.4	88.5
Week 96 (n= 36,24)	80.6	95.8
Week 156 (n= 17,16)	76.5	100

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 100 Response at Week 12

Top of page

End point title

Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 100 Response at Week 12 ^[14]

End point description

JIA ACR100 response was defined as a participant with at least 3 out of the 6 JIA core set variables with >= 100% improvement from baseline with no more than 1 of the remaining variables worsened by >= 30%. The efficacy analysis set included all participants who received at least 1dose of sarilumab.

End point type

Secondary

End point timeframe

Week 12

Notes
[14] - 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	6	5
Units: percentage of participants with response
number (not applicable)	0	0	33.3	40.0

No statistical analyses for this end point

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 100 Response at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 100 Response at Weeks 12, 24, 48, 96, and 156 ^[15]

End point description

End point type

Secondary

End point timeframe

Weeks 12, 24, 48, 96, and 156

Notes
[15] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	39	29
Units: percentage of participants with response
number (not applicable)
Week 12 (n= 39,29)	12.8	24.1
Week 24 (n= 39,27)	23.1	48.1
Week 48 (n= 38,26)	42.1	53.8
Week 96 (n= 36,24)	47.2	70.8
Week 156 (n= 17,16)	52.9	87.5

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Activity Joint Count-71, at Week 12

Top of page

End point title

Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Activity Joint Count-71, at Week 12 ^[16]

End point description

The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using visual analog scale (VAS), Childhood Health Questionnaire Disability Index (CHAQ-DI) and hs-CRP. Activity joint count-71 was calculated as sum (joints with active arthritis)*(71/number of joints with assessment). The efficacy analysis set included all participants who received at least 1 dose of sarilumab.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	6	5
Units: joint
arithmetic mean (standard error)	-14.40 ( 2.159 )	-11.20 ( 2.871 )	-16.50 ( 4.137 )	-14.40 ( 5.573 )

No statistical analyses for this end point

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Activity Joint Count-71, at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Activity Joint Count-71, at Weeks 12, 24, 48, 96, and 156 ^[17]

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156

Notes
[17] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	39	29
Units: joint
arithmetic mean (standard error)
Week 12 (n= 39,29)	-15.15 ( 1.511 )	-12.38 ( 1.519 )
Week 24 (n= 39,27)	-16.66 ( 1.497 )	-13.26 ( 1.575 )
Week 48 (n= 38,26)	-17.24 ( 1.547 )	-13.73 ( 1.618 )
Week 96 (n= 36,24)	-16.47 ( 1.682 )	-13.79 ( 1.751 )
Week 156 (n= 17,16)	-18.65 ( 2.334 )	-13.88 ( 2.495 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Limited Motion Joint Count, at Week 12

Top of page

End point title

Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Limited Motion Joint Count, at Week 12 ^[18]

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 12

Notes
[18] - 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	6	5
Units: joint
arithmetic mean (standard error)	-7.80 ( 2.083 )	-5.80 ( 2.267 )	-7.83 ( 2.600 )	-13.00 ( 4.219 )

No statistical analyses for this end point

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Limited Motion Joint Count, at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Limited Motion Joint Count, at Weeks 12, 24, 48, 96, and 156 ^[19]

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156

Notes
[19] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	39	29
Units: joint
arithmetic mean (standard error)
Week 12 (n= 39,29)	-9.71 ( 1.249 )	-9.21 ( 1.540 )
Week 24 (n= 39,27)	-10.40 ( 1.330 )	-10.63 ( 1.559 )
Week 48 (n= 38,26)	-10.99 ( 1.498 )	-10.73 ( 1.525 )
Week 96 (n= 36,24)	-11.14 ( 1.661 )	-10.42 ( 1.493 )
Week 156 (n= 17,16)	-11.29 ( 2.203 )	-11.81 ( 2.550 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Childhood Health Assessment Questionnaire Disability Index, at Week 12

Top of page

End point title

Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Childhood Health Assessment Questionnaire Disability Index, at Week 12 ^[20]

End point description

The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. CHAQ questionnaire consists of 30 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities. Each domain is scored on a 4-point scale ranges from 0 to 3: 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty) and 3 (unable to do). An additional response of “not applicable” is available to indicate participant is unable to perform activities. CHAQ-DI total score is sum of domain scores divided by number of domains that have a non-missing score. This overall score ranges from 0 (best) to 3 (worst). Higher scores indicate worse outcome. Efficacy population.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 12

Notes
[20] - 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	6	5
Units: units on a scale
arithmetic mean (standard error)	-0.80 ( 0.242 )	-1.08 ( 0.239 )	-0.42 ( 0.173 )	-0.75 ( 0.213 )

No statistical analyses for this end point

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Childhood Health Assessment Questionnaire Disability Index, at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Childhood Health Assessment Questionnaire Disability Index, at Weeks 12, 24, 48, 96, and 156 ^[21]

End point description

The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. CHAQ questionnaire consists of 30 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities. Each domain is scored on a 4-point scale ranges from 0 to 3: 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty) and 3 (unable to do). An additional response of “not applicable” is available to indicate participant is unable to perform activities. CHAQ-DI total score is sum of domain scores divided by number of domains that have a non-missing score. This overall score ranges from 0 (best) to 3 (worst). Higher scores indicate worse outcome. Efficacy population. n= number of participants analyzed at specific timepoints.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156

Notes
[21] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	39	29
Units: units on a scale
arithmetic mean (standard error)
Week 12 (n= 39,29)	-0.77 ( 0.092 )	-0.74 ( 0.113 )
Week 24 (n= 39,27)	-0.90 ( 0.096 )	-0.95 ( 0.132 )
Week 48 (n= 38,27)	-0.88 ( 0.084 )	-1.08 ( 0.119 )
Week 96 (n= 36,24)	-0.92 ( 0.109 )	-1.13 ( 0.136 )
Week 156 (n= 17,16)	-1.07 ( 0.163 )	-1.20 ( 0.169 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, C-Reactive Protein, at Week 12

Top of page

End point title

Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, C-Reactive Protein, at Week 12 ^[22]

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 12

Notes
[22] - 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	6	5
Units: mg/L
arithmetic mean (standard error)	-1.00 ( 1.130 )	-1.67 ( 1.139 )	-5.71 ( 3.633 )	-2.54 ( 1.845 )

No statistical analyses for this end point

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, C-Reactive Protein, at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, C-Reactive Protein, at Weeks 12, 24, 48, 96, and 156 ^[23]

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156

Notes
[23] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	39	29
Units: mg/L
arithmetic mean (standard error)
Week 12 (n= 39,27)	-3.84 ( 5.437 )	-20.66 ( 9.304 )
Week 24 (n= 37,29)	-8.54 ( 3.151 )	-11.72 ( 4.371 )
Week 48 (n= 38,27)	-9.93 ( 3.505 )	-12.57 ( 4.664 )
Week 96 (n= 36,23)	-9.39 ( 3.608 )	-13.88 ( 5.414 )
Week 156 (n= 16,16)	-5.10 ( 3.671 )	-12.30 ( 6.672 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Physician Global Assessment of Disease Activity, at Week 12

Top of page

End point title

Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Physician Global Assessment of Disease Activity, at Week 12 ^[24]

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 12

Notes
[24] - 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	6	5
Units: units on a scale
arithmetic mean (standard error)	-3.56 ( 0.969 )	-6.30 ( 0.397 )	-4.55 ( 0.509 )	-5.68 ( 1.163 )

No statistical analyses for this end point

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Physician Global Assessment of Disease Activity, at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Physician Global Assessment of Disease Activity, at Weeks 12, 24, 48, 96, and 156 ^[25]

End point description

The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. Physician global assessment of disease activity was assessed on an anchored 100 mm horizontal VAS score ranging from 0 to 100 where 0 is considered the best disease activity (no disease activity) and 100 the worst (most disease activity). Higher scores indicate worse outcome. The efficacy analysis set included all participants who received at least 1 dose of sarilumab. Here, n= number of participants analyzed at specific timepoints.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156

Notes
[25] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	39	29
Units: units on a scale
arithmetic mean (standard error)
Week 12 (n= 39,29)	-4.50 ( 0.248 )	-4.09 ( 0.367 )
Week 24 (n= 39,27)	-4.99 ( 0.237 )	-5.01 ( 0.341 )
Week 48 (n= 38,26)	-5.27 ( 0.263 )	-5.25 ( 0.321 )
Week 96 (n= 36,24)	-5.30 ( 0.306 )	-5.35 ( 0.347 )
Week 156 (n= 17,16)	-5.66 ( 0.396 )	-5.73 ( 0.437 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Participant/Parent Assessment of Overall Well-Being, at Week 12

Top of page

End point title

Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Participant/Parent Assessment of Overall Well-Being, at Week 12 ^[26]

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 12

Notes
[26] - 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	5	5	6	5
Units: units on a scale
arithmetic mean (standard error)	-3.30 ( 1.014 )	-3.16 ( 1.364 )	-3.05 ( 0.992 )	-5.00 ( 0.969 )

No statistical analyses for this end point

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Participant/Parent Assessment of Overall Well-Being, at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Participant/Parent Assessment of Overall Well-Being, at Weeks 12, 24, 48, 96, and 156 ^[27]

End point description

The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. Participant/parent assessment of overall well-being was rated on an anchored 100 mm horizontal VAS score ranging from 0 to 100 where 0 is considered the best disease activity (no disease activity) and 100 the worst (most disease activity). Higher scores indicate worse outcome. The efficacy analysis set included all participants who received at least 1 dose of sarilumab. Here, n= number of participants analyzed at specific timepoints.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156

Notes
[27] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	39	29
Units: units on a scale
arithmetic mean (standard error)
Week 12 (n= 39,29)	-3.73 ( 0.335 )	-4.01 ( 0.435 )
Week 24 (n= 39,27)	-4.38 ( 0.313 )	-4.39 ( 0.475 )
Week 48 (n= 38,27)	-4.21 ( 0.356 )	-4.64 ( 0.510 )
Week 96 (n= 36,23)	-4.36 ( 0.387 )	-5.09 ( 0.521 )
Week 156 (n= 17,16)	-4.19 ( 0.738 )	-5.01 ( 0.636 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 3: Mean Change From Baseline in Juvenile Arthritis Disease Activity Score (JADAS-27) at Week 12

Top of page

End point title

Cohorts 1 and 3: Mean Change From Baseline in Juvenile Arthritis Disease Activity Score (JADAS-27) at Week 12 ^[28]

End point description

The JADAS is used for assessment of disease activity and it includes 4 measures (physician global assessment of disease activity, parent/participant global assessment of well-being, count of joints with active disease and index of inflammation). JADAS total score is calculated as sum of scores of its 4 components. Total score ranges from 0 to 10 where 0= no activity and 10= maximum activity. Higher scores indicate better outcome. JADAS-27 count includes a count of 27 joints (cervical spine, elbows, wrists, metacarpophalangeal joints, proximal interphalangeal joints, hips, knees and ankles). Index of inflammation is determined by ESR or hs-CRP level. ESR normalized to 0-10 scale according to following formula: (ESR [mm/hour]‑20)/10. hs-CRP normalized to 0-10 scale according to following formula: (CRP [mg/L]‑10)/10. Clinical JADAS-27 is without CRP or ESR component. Efficacy population. Here, n= number of participants analyzed at baseline and Week 12 are reported.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 12

Notes
[28] - 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: Only participants treated in Cohorts 1 and 3 are analyzed for this endpoint.

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	7	6	6	9
Units: units on a scale
number (not applicable)
JADAS-27-ESR: Week 12 (n=5,5,6,4)	-15.4	-19.1	-20.0	-19.4
JADAS-27-CRP: Week 12 (n=7,6,6,9)	-16.04	-18.06	-18.48	-21.08
Clinical JADAS-27: Week 12 (n=7,6,6,9)	-16.06	-18.06	-18.27	-21.08

No statistical analyses for this end point

Secondary: Cohort 2: Mean Change From Baseline in Juvenile Arthritis Disease Activity Score at Weeks 12, 24, 48, 96, and 156

Top of page

End point title

Cohort 2: Mean Change From Baseline in Juvenile Arthritis Disease Activity Score at Weeks 12, 24, 48, 96, and 156 ^[29]

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156

Notes
[29] - 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: Only participants treated in Cohort 2 are analyzed for this endpoint.

End point values	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg
Number of subjects analysed	42	31
Units: units on a scale
number (not applicable)
JADAS-27-ESR: Week 12 (n= 37,29)	-18.9	-16.9
JADAS-27-ESR: Week 24 (n= 39,24)	-21.9	-18.3
JADAS-27-ESR: Week 48 (n= 38,26)	-22.3	-19.4
JADAS-27-ESR: Week 96 (n= 36,22)	-22.4	-20.4
JADAS-27-ESR: Week 156 (n= 16,14)	-23.2	-20.6
JADAS-27-CRP: Week 12 (n= 42,31)	-18.23	-16.31
JADAS-27-CRP: Week 24 (n= 42,31)	-20.92	-18.84
JADAS-27-CRP: Week 48 (n= 42,31)	-21.65	-19.44
JADAS-27-CRP: Week 96 (n= 42,31)	-21.90	-20.06
JADAS-27-CRP: Week 156 (n= 42,31)	-21.79	-20.21
Clinical JADAS-27: Week 12 (n= 42,31)	-17.93	-15.99
Clinical JADAS-27: Week 24 (n= 42,31)	-20.47	-17.96
Clinical JADAS-27: Week 48 (n= 42,31)	-20.98	-18.77
Clinical JADAS-27: Week 96 (n= 42,31)	-21.21	-19.46
Clinical JADAS-27: Week 156 (n= 42,31)	-21.21	-19.31

No statistical analyses for this end point

Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)

Top of page

End point title

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)

End point description

An adverse events (AEs) is any untoward medical occurrence in a participant or in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with the study treatment. An SAE is any untoward medical occurrence that at any dose results in death or is life-threatening or requires inpatient hospitalization or prolongation of existing hospitalization or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect or is an important medical event. TEAEs are defined as AEs that develop or worsen during the on-treatment period [that is, from the time of first dose of study treatment up to 6 weeks after the last administration of the study treatment]. The Safety analysis set included all participants who received at least 1 dose or part of a dose of the study treatment, analyzed according to the treatment actually received.

End point type

Secondary

End point timeframe

From the first administration of study treatment (Day 1) up to end of treatment period, maximum of 156 weeks for portions 1 and 2 and 96 weeks for portion 3

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	7	6	42	31	6	9
Units: participants
Any TEAE	7	6	40	30	5	9
Any treatment emergent SAE	2	0	3	3	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Local Site Reactions

Top of page

End point title

Number of Participants With Local Site Reactions

End point description

Participants were observed for at least 30 minutes after each study treatment administration either on site or at home and any local reactions were noted in the diary regardless of being clinically significant. The Safety analysis set included all participants who received at least 1 dose or part of a dose of the study treatment, analyzed according to the treatment actually received.

End point type

Secondary

End point timeframe

From the first administration of study treatment (Day 1) up to end of treatment period, maximum of 156 weeks for portions 1 and 2 and 96 weeks for portion 3

End point values	Cohort 1: >= 30 kg and <= 60 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 2: >= 30 kg and <= 60 kg	Cohort 2: < 30 kg and >= 10 kg	Cohort 3: >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg
Number of subjects analysed	7	6	42	31	6	9
Units: participants	1	0	21	19	3	1

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From the first administration of study treatment (Day 1) up to end of treatment period, maximum of 156 weeks for portions 1 and 2 and 96 weeks for portion 3.

Adverse event reporting additional description

Analysis was performed on the safety analysis set.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Cohort 1: >= 30 kg and <= 60 kg

Reporting group description

Participants with body weight >= 30 kg and <= 60 kg received sarilumab 2 mg/kg SC injection q2w for 12 weeks in core treatment phase (portion 1). Eligible participants continued to receive 2 mg/kg SC injection q2w until the selected dose was found and then switched to selected dose of 3 mg/kg SC injection q2w in extension phase (portion 2: up to 144 weeks and portion 3: up to 84 weeks).

Reporting group title

Cohort 2 (from Baseline): >= 30 kg and <= 60 kg

Reporting group description

Participants with body weight >= 30 kg and <= 60 kg received sarilumab 3 mg/kg SC injection q2w for 12 weeks in core treatment phase (portion 1).

Reporting group title

Cohort 3: < 30 kg and >= 10 kg

Reporting group description

Reporting group title

Cohort 1: < 30 kg and >= 10 kg

Reporting group description

Participants with body weight < 30 kg and >= 10 kg received sarilumab 2.5 mg/kg SC injection q2w for 12 weeks in core treatment phase (portion 1). Eligible participants continued to receive 2.5 mg/kg SC injection qw until the selected dose was found and then switched to selected dose of 4 mg/kg SC injection qw in extension phase (portion 2: up to 144 weeks and portion 3: up to 84 weeks).

Reporting group title

Cohort 2 (from Baseline): < 30 kg and >= 10 kg

Reporting group description

Participants with body weight < 30 kg and >= 10 kg received sarilumab 4 mg/kg SC injection q2w for 12 weeks in core treatment phase (portion 1).

Reporting group title

Cohort 2(Post dose-adjustment from Dose 1): <30 kg and >=10 kg

Reporting group description

Participants with body weight < 30 kg and >= 10 kg received sarilumab 4 mg/kg SC injection q2w for 144 weeks in portion 2.

Reporting group title

Cohort 2(Post dose-adjustment from Dose 3): <30 kg and >=10 kg

Reporting group description

Participants with body weight < 30 kg and >= 10 kg received sarilumab 4 mg/kg SC injection q2w for 84 weeks in portion 3.

Reporting group title

Cohort 2(Post dose-adjustment from Dose 3):>=30 kg and <=60 kg

Reporting group description

Participants with body weight >= 30 kg and <= 60 kg received sarilumab 3 mg/kg SC injection q2w for 84 weeks in portion 3.

Reporting group title

Cohort 2(Post dose-adjustment from Dose 1):>=30 kg and <=60 kg

Reporting group description

Participants with body weight >= 30 kg and <= 60 kg received sarilumab 3 mg/kg SC injection q2w for 144 weeks in portion 2.

Reporting group title

Cohort 3: >= 30 kg and <= 60 kg

Reporting group description

Participants with body weight >= 30 kg and <= 60 kg received sarilumab 2 mg/kg SC injection qw for 12 weeks in core treatment phase (portion 1). Eligible participants continued to receive 2 mg/kg SC injection qw until the selected dose was found and then switched to selected dose of 3 mg/kg SC injection qw in extension phase (portion 2: up to 144 weeks and portion 3: up to 84 weeks).

Serious adverse events	Cohort 1: >= 30 kg and <= 60 kg	Cohort 2 (from Baseline): >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 2 (from Baseline): < 30 kg and >= 10 kg	Cohort 2(Post dose-adjustment from Dose 1): <30 kg and >=10 kg	Cohort 2(Post dose-adjustment from Dose 3): <30 kg and >=10 kg	Cohort 2(Post dose-adjustment from Dose 3):>=30 kg and <=60 kg	Cohort 2(Post dose-adjustment from Dose 1):>=30 kg and <=60 kg	Cohort 3: >= 30 kg and <= 60 kg
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 7 (28.57%)	3 / 42 (7.14%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Ligament Rupture
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Meniscus Injury
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Inguinal Hernia
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0
Pancreatic Pseudocyst
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0
Pancreatitis Acute
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Tonsillar Hypertrophy
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Juvenile Idiopathic Arthritis
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Infections and infestations
Acute Sinusitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Infectious Mononucleosis
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Bone Tuberculosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 1: >= 30 kg and <= 60 kg	Cohort 2 (from Baseline): >= 30 kg and <= 60 kg	Cohort 3: < 30 kg and >= 10 kg	Cohort 1: < 30 kg and >= 10 kg	Cohort 2 (from Baseline): < 30 kg and >= 10 kg	Cohort 2(Post dose-adjustment from Dose 1): <30 kg and >=10 kg	Cohort 2(Post dose-adjustment from Dose 3): <30 kg and >=10 kg	Cohort 2(Post dose-adjustment from Dose 3):>=30 kg and <=60 kg	Cohort 2(Post dose-adjustment from Dose 1):>=30 kg and <=60 kg	Cohort 3: >= 30 kg and <= 60 kg
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	39 / 42 (92.86%)	9 / 9 (100.00%)	6 / 6 (100.00%)	29 / 31 (93.55%)	5 / 5 (100.00%)	5 / 5 (100.00%)	5 / 6 (83.33%)	4 / 4 (100.00%)	5 / 6 (83.33%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin Papilloma
subjects affected / exposed	1 / 7 (14.29%)	1 / 42 (2.38%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	0	0	0	0	0	0	0	1
Vascular disorders
Essential Hypertension
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
General disorders and administration site conditions
Administration Site Erythema
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Fatigue
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0
Gait Disturbance
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Injection Site Haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Injection Site Erythema
subjects affected / exposed	1 / 7 (14.29%)	4 / 42 (9.52%)	0 / 9 (0.00%)	0 / 6 (0.00%)	5 / 31 (16.13%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	20	0	0	7	0	0	0	0	0
Injection Site Pruritus
subjects affected / exposed	0 / 7 (0.00%)	3 / 42 (7.14%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	3	0	0	1	0	0	0	0	0
Pyrexia
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	6	0	1	0	0	1
Malaise
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Injection Site Urticaria
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
Injection Site Reaction
subjects affected / exposed	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	3	0	0	8	0	0	0	0	1
Immune system disorders
Allergy To Arthropod Bite
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	2 / 6 (33.33%)	5 / 31 (16.13%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	2	9	0	0	1	0	0
Epistaxis
subjects affected / exposed	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	4	0	0	2	0	0	0	0	0
Increased Bronchial Secretion
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Rhinitis Allergic
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	2 / 9 (22.22%)	2 / 6 (33.33%)	1 / 31 (3.23%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	3	2	1	0	1	0	0	0
Psychiatric disorders
Affective Disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Major Depression
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Investigations
Blood Pressure Systolic Decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0
Blood Bilirubin Increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Blood Alkaline Phosphatase Increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0	0
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	2	0	0	0	0	0	1	0	1
Alanine Aminotransferase Increased
subjects affected / exposed	1 / 7 (14.29%)	5 / 42 (11.90%)	1 / 9 (11.11%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	6	1	0	2	0	1	1	0	1
Eosinophil Count Increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	6 / 31 (19.35%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	9	0	0	0	0	0
Lymphocyte Count Increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	5	0	0	0	0	0
Monocyte Count Decreased
subjects affected / exposed	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0	2	0	0	0	0	0
Mean Cell Volume Decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0
Transaminases Increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Neutrophil Count Decreased
subjects affected / exposed	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0	6	0	0	0	0	0
Monocyte Count Increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0	2	0	0	0	0	0
Injury, poisoning and procedural complications
Accidental Overdose
subjects affected / exposed	0 / 7 (0.00%)	4 / 42 (9.52%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	1 / 5 (20.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	5	0	0	6	1	0	1	0	0
Arthropod Bite
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	1 / 6 (16.67%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	1	0	1	2	0	0	1	0	2
Ligament Sprain
subjects affected / exposed	1 / 7 (14.29%)	2 / 42 (4.76%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 4 (50.00%)	0 / 6 (0.00%)
occurrences all number	1	4	0	0	0	0	0	0	2	0
Hand Fracture
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Fall
subjects affected / exposed	0 / 7 (0.00%)	3 / 42 (7.14%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	3	0	0	3	0	0	0	0	0
Contusion
subjects affected / exposed	1 / 7 (14.29%)	3 / 42 (7.14%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	4	0	0	0	0	0	0	0	0
Thermal Burn
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Traumatic Haematoma
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Cardiac disorders
Cardiovascular Disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Headache
subjects affected / exposed	0 / 7 (0.00%)	2 / 42 (4.76%)	1 / 9 (11.11%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	4	2	0	4	0	1	0	0	1
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	3 / 7 (42.86%)	10 / 42 (23.81%)	6 / 9 (66.67%)	1 / 6 (16.67%)	15 / 31 (48.39%)	2 / 5 (40.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)
occurrences all number	3	23	9	1	78	2	0	0	1	2
Lymphopenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Lymphadenopathy
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0
Leukopenia
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	0	0	4	0	0	2	0	1
Ear and labyrinth disorders
Ear Pain
subjects affected / exposed	0 / 7 (0.00%)	3 / 42 (7.14%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	3	0	0	1	0	0	0	0	0
Eye disorders
Keratitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	1	0
Uveitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	1	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 7 (0.00%)	4 / 42 (9.52%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	4	0	0	1	0	0	0	0	1
Diarrhoea
subjects affected / exposed	0 / 7 (0.00%)	3 / 42 (7.14%)	2 / 9 (22.22%)	1 / 6 (16.67%)	4 / 31 (12.90%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	3	2	2	6	0	1	0	0	1
Dental Discomfort
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0
Constipation
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Aphthous Ulcer
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	1	0	0	2	0	0	1	0	1
Abdominal Pain Upper
subjects affected / exposed	0 / 7 (0.00%)	3 / 42 (7.14%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	5	0	0	2	0	0	0	0	0
Pulpless Tooth
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Nausea
subjects affected / exposed	0 / 7 (0.00%)	3 / 42 (7.14%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	4	0	0	2	0	0	0	0	0
Mouth Ulceration
subjects affected / exposed	1 / 7 (14.29%)	2 / 42 (4.76%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	4	0	0	1	0	0	0	0	0
Vomiting
subjects affected / exposed	0 / 7 (0.00%)	2 / 42 (4.76%)	1 / 9 (11.11%)	0 / 6 (0.00%)	3 / 31 (9.68%)	2 / 5 (40.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	3	1	0	4	2	2	0	0	3
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
Pityriasis Alba
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Alopecia
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Dermatitis Allergic
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	2 / 5 (40.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	2	0	0	0	0
Ingrowing Nail
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0
Acne
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Rash Pruritic
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Rash Papular
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
Rash
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	8	0	0	1	0	0
Skin Reaction
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Urticaria Chronic
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Urticaria
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	2	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Juvenile Idiopathic Arthritis
subjects affected / exposed	1 / 7 (14.29%)	3 / 42 (7.14%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 31 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	3	0	2	0	2	0	0	0	0
Arthralgia
subjects affected / exposed	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 9 (0.00%)	2 / 6 (33.33%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	3	0	2	3	0	0	0	0	0
Pain In Extremity
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	3	0	0	0	0	0
Infections and infestations
Conjunctivitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	6 / 31 (19.35%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0	8	0	0	0	0	0
Acute Sinusitis
subjects affected / exposed	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	2	0	0	1	0	0	0	0	1
Bronchitis
subjects affected / exposed	0 / 7 (0.00%)	4 / 42 (9.52%)	2 / 9 (22.22%)	1 / 6 (16.67%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	4	5	1	5	0	0	0	0	0
Covid-19
subjects affected / exposed	0 / 7 (0.00%)	4 / 42 (9.52%)	0 / 9 (0.00%)	0 / 6 (0.00%)	5 / 31 (16.13%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	4	0	0	5	0	1	0	0	0
Cellulitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	1	0	1
Conjunctivitis Bacterial
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Cystitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	4	0	0	0	0	0	0	0	0	1
Dengue Fever
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Ear Infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	2	0	0	0	0	0
Eczema Impetiginous
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Escherichia Urinary Tract Infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0
Gastritis Viral
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Gastroenteritis
subjects affected / exposed	1 / 7 (14.29%)	4 / 42 (9.52%)	0 / 9 (0.00%)	0 / 6 (0.00%)	9 / 31 (29.03%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	5	0	0	11	0	0	0	0	2
Gastrointestinal Bacterial Infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Infected Bite
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Impetigo
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0
Gastrointestinal Infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	2	0	0	0	0	0
Groin Abscess
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Infectious Mononucleosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Influenza
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0
Laryngitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Molluscum Contagiosum
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Otitis Externa
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	1	0
Oral Herpes
subjects affected / exposed	1 / 7 (14.29%)	1 / 42 (2.38%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	4	2	0	2	0	11	1	0	0
Oral Candidiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	2	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 7 (0.00%)	11 / 42 (26.19%)	3 / 9 (33.33%)	1 / 6 (16.67%)	17 / 31 (54.84%)	0 / 5 (0.00%)	3 / 5 (60.00%)	4 / 6 (66.67%)	0 / 4 (0.00%)	3 / 6 (50.00%)
occurrences all number	0	21	6	1	38	0	5	6	0	5
Otitis Media
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	4 / 31 (12.90%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	5	0	0	0	0	0
Pharyngitis Bacterial
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	0	1	0	0	0	0	0	1
Pharyngitis
subjects affected / exposed	1 / 7 (14.29%)	6 / 42 (14.29%)	0 / 9 (0.00%)	2 / 6 (33.33%)	1 / 31 (3.23%)	2 / 5 (40.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	6	0	3	1	4	0	0	0	0
Paronychia
subjects affected / exposed	0 / 7 (0.00%)	4 / 42 (9.52%)	0 / 9 (0.00%)	1 / 6 (16.67%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	5	0	1	1	0	0	0	0	0
Otitis Media Acute
subjects affected / exposed	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0	7	0	0	1	0	0
Pharyngitis Streptococcal
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0
Pharyngotonsillitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	6	0	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	2 / 6 (33.33%)
occurrences all number	0	0	0	0	2	0	0	0	0	2
Scarlet Fever
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Rhinitis
subjects affected / exposed	2 / 7 (28.57%)	4 / 42 (9.52%)	3 / 9 (33.33%)	1 / 6 (16.67%)	3 / 31 (9.68%)	1 / 5 (20.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	7	3	3	3	1	5	0	0	0
Respiratory Syncytial Virus Infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Pyelonephritis Acute
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Sinobronchitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Tinea Pedis
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	1	0
Sinusitis
subjects affected / exposed	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 31 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0	0	0	1	0	0	0
Tonsillitis
subjects affected / exposed	1 / 7 (14.29%)	2 / 42 (4.76%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 31 (6.45%)	0 / 5 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 6 (0.00%)
occurrences all number	1	2	0	0	2	0	1	1	1	0
Varicella
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	3	1	0	0	0	0
Urinary Tract Infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0	0
Upper Respiratory Tract Infection Bacterial
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 31 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Upper Respiratory Tract Infection
subjects affected / exposed	4 / 7 (57.14%)	6 / 42 (14.29%)	2 / 9 (22.22%)	2 / 6 (33.33%)	3 / 31 (9.68%)	0 / 5 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	3 / 4 (75.00%)	2 / 6 (33.33%)
occurrences all number	10	10	3	2	6	0	1	2	5	2
Tracheitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 31 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	1	0	1	0	0	0	0
Viral Upper Respiratory Tract Infection
subjects affected / exposed	1 / 7 (14.29%)	1 / 42 (2.38%)	1 / 9 (11.11%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	1	2	0	4	0	0	0	0	0
Viral Pharyngitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	1 / 31 (3.23%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	0
Metabolism and nutrition disorders
Vitamin D Deficiency
subjects affected / exposed	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 31 (9.68%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

06 Apr 2018

• To modify the study design to implement the amended Pediatric Investigations Plan approved by the European Medicines Agency. • To split the 12-week core treatment phase of the study into 2 portions: a dose-finding portion corresponding to the 12-week core treatment phase of the initial protocol where 3 ascending dose regimens will be tested in 36 participants; and a second portion where additional participants will receive the dose regimen selected from data of the first portion of the study in order to provide sufficient precision for PK parameters and PK-PD relationship assessments at that selected dose regimen. • To prolong the extension phase of the study from 92 weeks to 144 weeks for a total study duration of 166 weeks (per participant). • To increase the number of enrolled participants from 36 to 60 evaluable participants by 24 additional participants enrolled in the second portion of the study. • To revise the secondary efficacy endpoints. • To update the exclusion criteria section to better define the study population. • To incorporate several local protocol amendments that have already been approved, which address local health authorities and/or IRB requests related to the initial protocol.

13 Dec 2018

To update the stopping rules for Grade 4 neutropenia: The stopping rules for Grade 4 neutropenia was updated during the study after analysis of the 12-week core phase of the Portion 1 in order to provide the best chance for participants to benefit from treatment while continuously monitoring for safety events. Prior to the amendment, sarilumab had to be discontinued in case of Grade 4 neutropenia (absolute neutrophil count <0.5 Giga/liter) whether or not associated with signs of infection. Per the amendment, any Grade 4 neutropenia without infection led to temporary hold of treatment and the decision to resume sarilumab could be considered by the Investigator when absolute neutrophil count returned to >1.0 Giga/liter and based upon medical benefit-to-risk assessment. The rule stayed unchanged for any Grade 3 and 4 neutropenia associated with signs of infection (discontinuation) and Grade 3 neutropenia without infection (absolute neutrophil count ≥0.5 Giga/liter and <1.0 Giga/liter) (temporary hold).

12 Sep 2019

To increase the planned total number of enrolled participants (28 additional participants) to achieve a total of approximately 100 treated participants (based on health authority recommendations).

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: An Open-label, Sequential, Ascending, Repeated Dose-finding Study of Sarilumab, Administered with Subcutaneous (SC) Injection, in Children and Adolescents, Aged 2 to 17 Years, with Polyarticular-course Juvenile Idiopathic Arthritis (pcJIA) Followed by an Extension Phase

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximum Serum Concentration (Cmax) at Steady State of Sarilumab

Primary: Maximum Serum Concentration (Cmax) at Steady State of Sarilumab

Primary: Area Under the Serum Concentration Versus Time Curve Using the Trapezoidal Method During a Dose Interval (AUC0-t) at Steady State of Sarilumab

Primary: Area Under the Serum Concentration Versus Time Curve Using the Trapezoidal Method During a Dose Interval (AUC0-t) at Steady State of Sarilumab

Primary: Concentration Before Treatment Administration During Repeated Dosing (Ctrough) at Steady State of Sarilumab

Primary: Concentration Before Treatment Administration During Repeated Dosing (Ctrough) at Steady State of Sarilumab

Secondary: Cohorts 1 and 3: Change From Baseline in High-Sensitivity C-reactive Protein (hs-CRP) at Week 12

Secondary: Cohorts 1 and 3: Change From Baseline in High-Sensitivity C-reactive Protein (hs-CRP) at Week 12

Secondary: Cohort 2: Change From Baseline in High-Sensitivity C-reactive Protein at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Change From Baseline in High-Sensitivity C-reactive Protein at Weeks 12, 24, 48, 96, and 156

Secondary: Change From Baseline in Interleukin-6 (IL-6) at Week 12

Secondary: Change From Baseline in Interleukin-6 (IL-6) at Week 12

Secondary: Change From Baseline in Total Soluble Interleukin-6 Receptor (sIL-6R) at Week 12

Secondary: Change From Baseline in Total Soluble Interleukin-6 Receptor (sIL-6R) at Week 12

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology (JIA ACR) 30 Response at Week 12

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology (JIA ACR) 30 Response at Week 12

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 30 Response at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 30 Response at Weeks 12, 24, 48, 96, and 156

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 50 Response at Week 12

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 50 Response at Week 12

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 50 Response at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 50 Response at Weeks 12, 24, 48, 96, and 156

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 70 Response at Week 12

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 70 Response at Week 12

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 70 Response at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 70 Response at Weeks 12, 24, 48, 96, and 156

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 90 Response at Week 12

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 90 Response at Week 12

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 90 Response at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 90 Response at Weeks 12, 24, 48, 96, and 156

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 100 Response at Week 12

Secondary: Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 100 Response at Week 12

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 100 Response at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 100 Response at Weeks 12, 24, 48, 96, and 156

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Activity Joint Count-71, at Week 12

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Activity Joint Count-71, at Week 12

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Activity Joint Count-71, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Activity Joint Count-71, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Limited Motion Joint Count, at Week 12

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Limited Motion Joint Count, at Week 12

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Limited Motion Joint Count, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Limited Motion Joint Count, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Childhood Health Assessment Questionnaire Disability Index, at Week 12

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Childhood Health Assessment Questionnaire Disability Index, at Week 12

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Childhood Health Assessment Questionnaire Disability Index, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Childhood Health Assessment Questionnaire Disability Index, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, C-Reactive Protein, at Week 12

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, C-Reactive Protein, at Week 12

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, C-Reactive Protein, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, C-Reactive Protein, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Physician Global Assessment of Disease Activity, at Week 12

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Physician Global Assessment of Disease Activity, at Week 12

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Physician Global Assessment of Disease Activity, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Physician Global Assessment of Disease Activity, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Participant/Parent Assessment of Overall Well-Being, at Week 12

Secondary: Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Participant/Parent Assessment of Overall Well-Being, at Week 12

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Participant/Parent Assessment of Overall Well-Being, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Participant/Parent Assessment of Overall Well-Being, at Weeks 12, 24, 48, 96, and 156

Secondary: Cohorts 1 and 3: Mean Change From Baseline in Juvenile Arthritis Disease Activity Score (JADAS-27) at Week 12

Secondary: Cohorts 1 and 3: Mean Change From Baseline in Juvenile Arthritis Disease Activity Score (JADAS-27) at Week 12

Secondary: Cohort 2: Mean Change From Baseline in Juvenile Arthritis Disease Activity Score at Weeks 12, 24, 48, 96, and 156

Secondary: Cohort 2: Mean Change From Baseline in Juvenile Arthritis Disease Activity Score at Weeks 12, 24, 48, 96, and 156

Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)

Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)

Secondary: Number of Participants With Local Site Reactions

Secondary: Number of Participants With Local Site Reactions

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Clinical Trial Results:
An Open-label, Sequential, Ascending, Repeated Dose-finding Study of Sarilumab, Administered with Subcutaneous (SC) Injection, in Children and Adolescents, Aged 2 to 17 Years, with Polyarticular-course Juvenile Idiopathic Arthritis (pcJIA) Followed by an Extension Phase