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Clinical Trial Results:
A 24-Week Randomized Double-Blind, Placebo Controlled Withdrawal Trial With a 16-Week Open-Label Lead-In Phase, and 64-Week Open-Label Follow-Up, to Evaluate the Efficacy and Safety of Tocilizumab in Patients with Active Polyarticular Juvenile Idiopathic Arthritis

Summary
EudraCT number	2009-011593-15
Trial protocol	GB DE IT ES BE NL FR
Global end of trial date	28 Jan 2013

Results information
Results version number	v1(current)
This version publication date	01 Jun 2016
First version publication date	01 Jun 2016
Other versions

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

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Trial information

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Sponsor protocol code

WA19977

ISRCTN number

US NCT number

NCT00988221

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland,

Public contact

Roche Trial Information Hotline, Roche Trial Information Hotline, 41 61 6878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, Roche Trial Information Hotline, 41 61 6878333, global.trial_information@roche.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000309-PIP01-08

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

28 Jan 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Jan 2013

Was the trial ended prematurely?

Main objective of the trial

This 3-part study evaluated the efficacy and safety of tocilizumab in patients with active polyarticular-course juvenile idiopathic arthritis who have an inadequate response to, or were intolerant of methotrexate. In Part I of the study, all patients received intravenous (iv) infusions of tocilizumab (8 milligrams per kilogram [mg/kg] for patients greater than or equal to [≥]30 kg, 8 mg/kg or 10 mg/kg for patients less than [<]30 kg) every 4 weeks for 16 weeks. In Part II of the study, patients with an adequate response in Part I were randomized to receive either tocilizumab at the same dose as in Part I or placebo every 4 weeks for up to 24 weeks. In Part III of the study, patients received tocilizumab at the same dose as in Part I every 4 weeks for up to another 64 weeks. Standard of care therapy with or without non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate was continued throughout the study.

Protection of trial subjects

The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures described in the protocol.

Background therapy

Evidence for comparator

Actual start date of recruitment

14 Oct 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 23

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

United Kingdom: 6

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

France: 10

Country: Number of subjects enrolled

Germany: 14

Country: Number of subjects enrolled

Italy: 7

Country: Number of subjects enrolled

Australia: 4

Country: Number of subjects enrolled

Argentina: 19

Country: Number of subjects enrolled

Canada: 10

Country: Number of subjects enrolled

Brazil: 18

Country: Number of subjects enrolled

Mexico: 12

Country: Number of subjects enrolled

Peru: 11

Country: Number of subjects enrolled

Russian Federation: 27

Country: Number of subjects enrolled

United States: 14

Worldwide total number of subjects

188

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)

101

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

In Part I, patients received either tocilizumab 8 or 10 mg/kg. In Part II, eligible patients were randomized to receive placebo or the same dose of tocilizumab as in Part I of the study. In Part III, patients received the same dose of tocilizumab as in Part I of the study, with adjustments based on weight and change in weight from Baseline.

Period 1 title

Part I

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Tocilizumab 10 mg/kg in Patients Weighing <30 kg

Arm description

Patients received tocilizumab 10 mg/kg intravenously every 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

RO4877533

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab intravenously every 4 weeks.

Tocilizumab 8 mg/kg in Patients Weighing < 30 kg

Arm description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg

Arm description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Tocilizumab 8 or 10 mg/kg

Arm description

Patients received tocilizumab 8 or 10 mg/kg intravenously every 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab 8 or 10 mg/kg intravenously every 4 weeks.

Number of subjects in period 1	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Started	35	34	119	188
Completed	31	24	111	166
Not completed	4	10	8	22
Insufficient therapeutic response	4	6	5	15
Adverse event, non-fatal	-	1	2	3
Refused treatment	-	2	1	3
Lost to follow-up	-	1	-	1

Period 2 title

Part II

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Tocilizumab 10 mg/kg in Patients Weighing < 30 kg

Arm description

Patients received tocilizumab 10 mg/kg intravenously every 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab 10 mg/kg intravenously every 4 weeks.

Tocilizumab 8 mg/kg in Patients Weighing < 30 kg

Arm description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg

Arm description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Placebo

Arm description

Patients received placebo to tocilizumab intravenously every 4 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received placebo to tocilizumab intravenously every 4 weeks.

Number of subjects in period 2	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Placebo
Started	16	11	55	84
Completed	15	11	52	81
Not completed	1	0	3	3
Consent withdrawn by subject	-	-	2	1
Adverse event, non-fatal	1	-	-	2
Reason not specified	-	-	1	-

Period 3 title

Part III

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Tocilizumab 10 mg/kg in Patients Weighing < 30 kg

Arm description

Patients received tocilizumab 10 mg/kg intravenously every 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab 10 mg/kg intravenously every 4 weeks.

Tocilizumab 8 mg/kg in Patients Weighing < 30 kg

Arm description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg

Arm description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

All Tocilizumab Patients

Arm description

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Patients received tocilizumab 8 or 10 mg/kg intravenously every 4 weeks.

Number of subjects in period 3	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients
Started	30	24	106	160
Completed	29	23	103	160
Not completed	1	1	3	0
Insufficient therapeutic response	-	1	1	-
Adverse event, non-fatal	1	-	1	-
Refused treatment	-	-	1	-

Baseline characteristics

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Reporting group title

Part I

Reporting group description

In Part I, patients received either tocilizumab 8 or 10 mg/kg.

Reporting group values	Part I	Total
Number of subjects	188	188
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	11 ( 4.01 )	-
Gender categorical
Units: Subjects
Female	144	144
Male	44	44

Subject analysis set title

All Tocilizumab Participants

Subject analysis set type

Full analysis

Subject analysis set description

All participants who received 8 or 10 mg/kg of tocilizumab

Subject analysis set title

Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Patients weighing < 30 kg at baseline receiving tocilizumab 10 mg/kg whose body weight increased to ≥ 30 kg and ≥ 5 kg over baseline body weight for 3 consecutive visits had the tocilizumab dose reduced to 8 mg/kg.

Subject analysis sets values	All Tocilizumab Participants	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects	188	7
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	11 ( 4.01 )	( )
Gender categorical
Units: Subjects
Female	144
Male	44

End points

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Reporting group title

Tocilizumab 10 mg/kg in Patients Weighing <30 kg

Reporting group description

Patients received tocilizumab 10 mg/kg intravenously every 4 weeks.

Reporting group title

Tocilizumab 8 mg/kg in Patients Weighing < 30 kg

Reporting group description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Reporting group title

Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg

Reporting group description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Reporting group title

Tocilizumab 8 or 10 mg/kg

Reporting group description

Patients received tocilizumab 8 or 10 mg/kg intravenously every 4 weeks.

Reporting group title

Tocilizumab 10 mg/kg in Patients Weighing < 30 kg

Reporting group description

Patients received tocilizumab 10 mg/kg intravenously every 4 weeks.

Reporting group title

Tocilizumab 8 mg/kg in Patients Weighing < 30 kg

Reporting group description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Reporting group title

Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg

Reporting group description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Reporting group title

Placebo

Reporting group description

Patients received placebo to tocilizumab intravenously every 4 weeks.

Reporting group title

Tocilizumab 10 mg/kg in Patients Weighing < 30 kg

Reporting group description

Patients received tocilizumab 10 mg/kg intravenously every 4 weeks.

Reporting group title

Tocilizumab 8 mg/kg in Patients Weighing < 30 kg

Reporting group description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Reporting group title

Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg

Reporting group description

Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

Reporting group title

All Tocilizumab Patients

Reporting group description

Subject analysis set title

All Tocilizumab Participants

Subject analysis set type

Full analysis

Subject analysis set description

All participants who received 8 or 10 mg/kg of tocilizumab

Subject analysis set title

Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: Percent of Patients With a Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology 30 (ACR30) Flare in Part II of the Study (Weeks 16-40)

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End point title

Percent of Patients With a Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology 30 (ACR30) Flare in Part II of the Study (Weeks 16-40) ^[1] ^[2]

End point description

JIA ACR30 flare is defined as a ≥ 30% worsening of 3 of 6 variables and no more than 1 of the remaining variables improving > 30%. The 6 variables are physician global assessment of disease activity (worsening of 20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (worsening of 20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]). Patients who withdrew or who took escape medication are classified as flared. The analysis used the Cochran-Mantel-Haenszel test with the stratification variables background use of methotrexate and oral corticosteroids applied at Week 16.

End point type

Primary

End point timeframe

Week 16 through Week 40

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: This endpoint data were not analyzed for all baseline period arms.
[2] - 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: This endpoint data were not analyzed for all baseline period arms.

End point values	Placebo	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	81	82
Units: Percent of patients
number (confidence interval 95%)	48.1 (37 to 59)	25.6 (16 to 35)

No statistical analyses for this end point

Secondary: Percent of Patients Achieving JIA ACR30/50/70/90 Responses in Part I of the Study (Baseline to Week 16)

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End point title

Percent of Patients Achieving JIA ACR30/50/70/90 Responses in Part I of the Study (Baseline to Week 16)

End point description

A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 VAS), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the CHAQ, 30 questions, 8 domains, 0[best]-3[worst]).

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	35	34	119	188
Units: Percent of patients
number (not applicable)
ACR30 response	88.6	76.5	93.3	89.4
ACR50 response	80	70.6	87.4	83
ACR70 response	62.9	41.2	68.1	62.2
ACR90 response	31.4	23.5	25.2	26.1

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at the End of Part I of the Study (Week 16)

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End point title

Percent Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at the End of Part I of the Study (Week 16)

End point description

The patient’s treating physician provides a rating of the patient’s arthritis disease activity on a 0 to 100 mm horizontal scale. The extreme left end of the line represents ‘arthritis inactive’ (ie, symptom-free and no arthritis symptoms) and the extreme right end represents ‘arthritis very active’. A higher score indicates more disease activity. A negative change score indicates improvement.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	35	34	119	188
Units: percent change
arithmetic mean (standard deviation)	-61.48 ( 48.779 )	-65.2 ( 26.17 )	-72.61 ( 25.977 )	-69.19 ( 31.824 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at the End of Part I of the Study (Week 16)

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End point title

Percent Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at the End of Part I of the Study (Week 16)

End point description

The patient or parent/guardian, as appropriate, provides a rating of the patient’s well-being on a 0 to 100 mm horizontal scale. The extreme left end of the line represents ‘very well’ (ie, symptom-free and no arthritis disease activity) and the extreme right end represents ‘very poor’ (ie, maximum arthritis disease activity). A higher score indicates poorer well-being. A negative change score indicates improvement.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	35	34	119	188
Units: Percent change
arithmetic mean (standard deviation)	-31.65 ( 120.268 )	-55.56 ( 42.092 )	-53.34 ( 58.686 )	-49.46 ( 72.92 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Active Arthritis at the End of Part I of the Study (Week 16)

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End point title

Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Active Arthritis at the End of Part I of the Study (Week 16)

End point description

Joints with active arthritis are defined as joints with swelling present or pain present and limitation of motion. The maximum possible number of joints with active arthritis is 71. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient’s efficacy and safety data. A negative change score indicates improvement.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	35	34	119	188
Units: Percent change
arithmetic mean (standard deviation)	-63.36 ( 43.272 )	-55.57 ( 44.876 )	-72.96 ( 33.915 )	-68.15 ( 38.246 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at the End of Part I of the Study (Week 16)

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End point title

Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at the End of Part I of the Study (Week 16)

End point description

Joints with limitation of movement are defined as joints with limitation of motion. The maximum possible number of joints with limitation of movement is 67. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient’s efficacy and safety data. A negative change score indicates improvement.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	35	34	119	188
Units: Percent change
arithmetic mean (standard deviation)	-61.83 ( 34.726 )	-49.87 ( 48.091 )	-65.96 ( 30.134 )	-62.42 ( 34.955 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the JIA ACR Component Score ESR at the End of Part I of the Study (Week 16)

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End point title

Percent Change From Baseline in the JIA ACR Component Score ESR at the End of Part I of the Study (Week 16)

End point description

Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory. A negative change score indicates improvement.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	35	34	119	188
Units: Percent change
arithmetic mean (standard deviation)	-70.98 ( 24.53 )	-21.84 ( 159.592 )	-70.87 ( 33.4 )	-62.54 ( 73.384 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the JIA ACR Component Score Functional Ability at the End of Part I of the Study (Week 16)

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End point title

Percent Change From Baseline in the JIA ACR Component Score Functional Ability at the End of Part I of the Study (Week 16)

End point description

Functional ability is assessed with the Childhood Health Assessment Questionnaire disability index (CHAQ-DI) which consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. If aids and devices listed in the questionnaire or assistance from a person are required to perform a task, a domain score of 0 or 1 is increased to 2; if the domain score is 2 or 3, the domain score is not adjusted. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A higher score indicates less ability. A negative change score indicates improvement.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	35	34	119	188
Units: percent change
arithmetic mean (standard deviation)	-54.48 ( 37.214 )	-46.16 ( 50.961 )	-49.07 ( 45.048 )	-49.62 ( 44.573 )

No statistical analyses for this end point

Secondary: Juvenile Arthritis Disease Activity Score (JADAS-27) at the End of Part I of the Study (Week 16)

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End point title

Juvenile Arthritis Disease Activity Score (JADAS-27) at the End of Part I of the Study (Week 16)

End point description

The JADAS-27 is derived from the following components: Physician’s global assessment of disease activity on a 0-100 mm visual analog scale (VAS)/10, patient/parent’s global assessment of overall well-being on a 0-100 mm VAS/10, normalized erythrocyte sedimentation rate (ESR) (if ESR is ≤ 20 then set to 0, if ≥ 120 then set to 10, and if > 20 and < 120 then apply formula [ESR-20]/10), and number of joints (maximum of 27) with active arthritis (cervical spine, left/right elbow, left/right wrist, left/right metacarpophalangeal (MCP) 1-3, left/right proximal interphalangeal joint (PIP) 1-5, left/right hips, left/right knee and left/right ankle). The scores for the first 3 components range from 0-10; the score for the final component ranges from 0-27. The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity.

End point type

Secondary

End point timeframe

Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	35	34	119	188
Units: Units on a scale
arithmetic mean (standard deviation)	9.08 ( 8.882 )	12.25 ( 10.277 )	7.83 ( 7.122 )	8.82 ( 8.198 )

No statistical analyses for this end point

Secondary: Pain Visual Analogue Scale (VAS) Score at the End of Part I of the Study (Week 16)

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End point title

Pain Visual Analogue Scale (VAS) Score at the End of Part I of the Study (Week 16)

End point description

End point type

Secondary

End point timeframe

Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	35	34	119	188
Units: mm
arithmetic mean (standard deviation)	21.9 ( 21.66 )	24.1 ( 23.94 )	20.3 ( 21.13 )	21.2 ( 21.65 )

No statistical analyses for this end point

Secondary: Percentage of Patients With Inactive Disease at the End of Part I of the Study (Week 16)

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End point title

Percentage of Patients With Inactive Disease at the End of Part I of the Study (Week 16)

End point description

A patient is judged to have inactive disease if all of the following criteria are met: Number of joints with active arthritis = 0; absence of active uveitis, defined by the adverse event preferred terms ‘uveitis’ and ‘intermediate uveitis’; normal erythrocyte sedimentation rate (< 20 mm/hour regardless of age and sex); and physician’s global assessment of overall well-being visual analog scale score ≤ 10.

End point type

Secondary

End point timeframe

Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	35	34	119	188
Units: Percentage of patients
number (not applicable)	20	8.8	18.5	17

No statistical analyses for this end point

Secondary: Percentage of Patients With an Elevated C-reactive Protein Concentration at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

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End point title

Percentage of Patients With an Elevated C-reactive Protein Concentration at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

End point description

C-reactive protein (CRP), an acute phase protein, was measured in blood samples with a high-sensitivity CRP (hs-CRP) test using laser nephelometry. CRP levels higher than 10 milligrams per deciliter (mg/dL) are considered to be elevated levels.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	13	19	46	78
Units: Percentage of patients
number (not applicable)	76.9	63.2	87	79.5

No statistical analyses for this end point

Secondary: Percentage of Patients With an Elevated ESR at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

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End point title

Percentage of Patients With an Elevated ESR at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

End point description

Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	23	26	73	122
Units: Percent of patients
number (not applicable)	82.6	57.7	87.7	80.3

No statistical analyses for this end point

Secondary: Percentage of Patients With an Elevated Platelet Count at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

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End point title

Percentage of Patients With an Elevated Platelet Count at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

End point description

Platelets were measured in blood samples taken from the patients.Platelet counts above 400,00 are considered to be elevated.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	13	18	43	74
Units: Percentage of patients
number (not applicable)	84.6	55.6	86	78.4

No statistical analyses for this end point

Secondary: Percentage of Patients With an Elevated White Blood Count at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

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End point title

Percentage of Patients With an Elevated White Blood Count at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

End point description

White blood cells were measured in blood samples taken from the patients. Counts of more than 10,500 cells per microliter are considered to be elevated levels.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	3	3	2	8
Units: Percentage of patients
number (not applicable)	66.7	66.7	100	75

No statistical analyses for this end point

Secondary: Percent of Patients Achieving JIA ACR30/50/70/90 Responses at the End of Part II of the Study (Week 40)

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End point title

Percent of Patients Achieving JIA ACR30/50/70/90 Responses at the End of Part II of the Study (Week 40) ^[3]

End point description

A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]). The analysis used the Cochran-Mantel-Haenszel test with the stratification variables background use of methotrexate and oral corticosteroids applied at Week 16.

End point type

Secondary

End point timeframe

Week 40

Notes
[3] - 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: This endpoint data were not analyzed for all baseline period arms.

End point values	Placebo	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	81	82
Units: Percent of patients
number (confidence interval 95%)
ACR30 response	54.3 (43 to 65)	74.4 (65 to 84)
ACR50 response	51.9 (41 to 63)	73.2 (64 to 83)
ACR70 response	42 (31 to 53)	64.6 (54 to 75)
ACR90 response	23.5 (14 to 33)	45.1 (34 to 56)

No statistical analyses for this end point

Secondary: Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at the End of Part II of the Study (Week 40)

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End point title

Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at the End of Part II of the Study (Week 40) ^[4]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 40

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Placebo	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	81	82
Units: Units on a scale
arithmetic mean (standard deviation)	-38.2 ( 24.77 )	-45.6 ( 21.47 )

No statistical analyses for this end point

Secondary: Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at the End of Part II of the Study (Week 40)

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End point title

Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at the End of Part II of the Study (Week 40) ^[5]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 40

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Placebo	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	81	82
Units: Units on a scale
arithmetic mean (standard deviation)	-32.4 ( 28.57 )	-31.1 ( 28.52 )

No statistical analyses for this end point

Secondary: Change From Baseline in the JIA ACR Component Score Number of Joints With Active Arthritis at the End of Part II of the Study (Week 40)

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End point title

Change From Baseline in the JIA ACR Component Score Number of Joints With Active Arthritis at the End of Part II of the Study (Week 40) ^[6]

End point description

Joints with active arthritis are defined as joints with swelling present or pain present and limitation of motion. The maximum number of joints with active arthritis is 71. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient’s efficacy and safety data. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.

End point type

Secondary

End point timeframe

Baseline to Week 40

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Placebo	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	81	82
Units: Joints
arithmetic mean (standard deviation)	-11.5 ( 12.77 )	-14.5 ( 11.14 )

No statistical analyses for this end point

Secondary: Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at the End of Part II of the Study (Week 40)

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End point title

Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at the End of Part II of the Study (Week 40) ^[7]

End point description

Joints with limitation of movement are defined as joints with limitation of motion. The maximum number of joints with limitation of movement is 67. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient’s efficacy and safety data. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.

End point type

Secondary

End point timeframe

Baseline to Week 40

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Placebo	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	81	82
Units: Joints
arithmetic mean (standard deviation)	-8.1 ( 9.9 )	-10.2 ( 8.97 )

No statistical analyses for this end point

Secondary: Change From Baseline in the JIA ACR Component Score ESR at the End of Part II of the Study (Week 40)

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End point title

Change From Baseline in the JIA ACR Component Score ESR at the End of Part II of the Study (Week 40) ^[8]

End point description

Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.

End point type

Secondary

End point timeframe

Baseline to Week 40

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Placebo	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	81	82
Units: mm/hour
arithmetic mean (standard deviation)	-14 ( 28.46 )	-25.2 ( 21.97 )

No statistical analyses for this end point

Secondary: Change From Baseline in the JIA ACR Component Score CHAQ-DI at the End of Part II of the Study (Week 40)

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End point title

Change From Baseline in the JIA ACR Component Score CHAQ-DI at the End of Part II of the Study (Week 40) ^[9]

End point description

The Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI), as a measure of functional ability, consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A higher score indicates less ability. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.

End point type

Secondary

End point timeframe

Baseline to Week 40

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Placebo	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	81	82
Units: Units on a scale
arithmetic mean (standard deviation)	-0.724 ( 0.6905 )	-0.804 ( 0.6534 )

No statistical analyses for this end point

Secondary: Change From Baseline in the Pain VAS Score at the End of Part II of the Study (Week 40)

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End point title

Change From Baseline in the Pain VAS Score at the End of Part II of the Study (Week 40) ^[10]

End point description

The patient or parent/guardian, as appropriate, provides a rating of the patient’s pain (also called a discomfort index) on a 0 to 100 mm horizontal scale. The extreme left end of the line represents ‘no pain’ and the extreme right end represents ‘very extreme pain’. A higher score indicates more pain. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward (LOCF) imputation for missing values. The analysis was adjusted for the randomization stratification factors background use of methotrexate and background use of oral corticosteroids, and the pain visual analog scale score at Baseline. The adjusted means from the fitted model are presented.

End point type

Secondary

End point timeframe

Baseline to Week 40

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Placebo	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	81	82
Units: Units on a scale
arithmetic mean (standard deviation)	-30.2 ( 27.12 )	-31.5 ( 31.76 )

Statistical Analysis 1

Comparison groups

Placebo v Tocilizumab 8 or 10 mg/kg

Number of subjects included in analysis

163

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0076

Method

ANOVA

Parameter type

Mean difference (final values)

Point estimate

-10.2

Confidence interval

level

95%

sides

2-sided

lower limit

-17.6

upper limit

-2.7

Secondary: Percent of Patients With Inactive Disease at the End of Part II of the Study (Week 40)

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End point title

Percent of Patients With Inactive Disease at the End of Part II of the Study (Week 40) ^[11]

End point description

End point type

Secondary

End point timeframe

Week 40

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Placebo	Tocilizumab 8 or 10 mg/kg
Number of subjects analysed	81	82
Units: Percent of patients
number (confidence interval 95%)	17.3 (9 to 26)	36.6 (26 to 47)

Statistical Analysis 1

Comparison groups

Tocilizumab 8 or 10 mg/kg v Placebo

Number of subjects included in analysis

163

Analysis specification

Pre-specified

Analysis type

other

P-value

= 1 ^[12]

Method

Cochran-Mantel-Haenszel

Parameter type

weighted difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[12] - 1.000 is used here as the test was considered as not significant due to the break in the hierarchical testing chain.

Secondary: Percent of Patients Achieving JIA ACR30/50/70/90 Responses at Weeks 2, 52, and 104

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End point title

Percent of Patients Achieving JIA ACR30/50/70/90 Responses at Weeks 2, 52, and 104

End point description

A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]).

End point type

Secondary

End point timeframe

Week 2 to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	9	11	55	82	7
Units: Percent of patients
number (not applicable)
Week 2 - ACR30 Response	55.6	45.5	54.5	52.4	42.9
Week 2 - ACR50 Response	33.3	18.2	34.5	32.9	42.9
Week 2 - ACR70 Response	11.1	9.1	12.7	11	0
Week 2 - ACR90 Response	0	0	0	0	0
Week 52 - ACR30 Response	100	100	96.4	97.6	100
Week 52 - ACR50 Response	100	90.9	94.5	95.1	100
Week 52 - ACR70 Response	100	72.7	87.3	86.6	85.7
Week 52 - ACR90 Response	88.9	54.5	65.5	65.9	57.1
Week 104 - ACR30 Response	100	90.9	94.5	95.1	100
Week 104 - ACR50 Response	100	90.9	87.3	90.2	100
Week 104 - ACR70 Response	88.9	90.9	83.6	86.6	100
Week 104 - ACR90 Response	88.9	72.7	67.3	70.7	71.4

No statistical analyses for this end point

Secondary: Percent of Patients With 4 Baseline Disease Characteristics Achieving JIA ACR30/50/70/90 Responses at Week 104

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End point title

Percent of Patients With 4 Baseline Disease Characteristics Achieving JIA ACR30/50/70/90 Responses at Week 104

End point description

A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]).

End point type

Secondary

End point timeframe

Week 2 to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	9	11	55	82	7
Units: Percent of patients
number (not applicable)
Previous Biologic Use: Yes - ACR30 (n=1,0,25,27,1)	100	0	96	96.3	100
Previous Biologic Use: Yes - ACR50 (n=1,0,25,27,1)	100	0	80	81.5	100
Previous Biologic Use: Yes - ACR70 (n=1,0,25,27,1)	0	0	72	70.4	100
Previous Biologic Use: Yes - ACR90 (n=1,0,25,27,1)	0	0	48	48.1	100
Previous Biologic Use: No - ACR30 (n=8,11,30,55,6)	100	90.9	93.3	94.5	100
Previous Biologic Use: No - ACR50 (n=8,11,30,55,6)	100	90.9	93.3	94.5	100
Previous Biologic Use: No - ACR70 (n=8,11,30,55,6)	100	90.9	93.3	94.5	100
Previous Biologic Use: No - ACR90 (n=8,11,30,55,6)	100	72.7	83.3	81.8	66.7
Methotrexate Use: Yes - ACR30 (n=7,11,42,67,7)	100	90.9	95.2	95.5	100
Methotrexate Use: Yes - ACR50 (n=7,11,42,67,7)	100	90.9	88.1	91	100
Methotrexate Use: Yes - ACR70 (n=7,11,42,67,7)	100	90.9	83.3	88.1	100
Methotrexate Use: Yes - ACR90 (n=7,11,42,67,7)	100	72.7	73.8	76.1	71.4
Methotrexate Use: No - ACR30 (n=2,0,13,15,0)	100	0	92.3	93.3	0
Methotrexate Use: No - ACR50 (n=2,0,13,15,0)	100	0	84.6	86.7	0
Methotrexate Use: No - ACR70 (n=2,0,13,15,0)	50	0	84.6	80	0
Methotrexate Use: No - ACR90 (n=2,0,13,15,0)	50	0	46.2	46.7	0
Oral Corticosteroid Use: Yes -ACR30(n=2,5,23,33,3)	100	80	91.3	90.9	100
Oral Corticosteroid Use: Yes -ACR50(n=2,5,23,33,3)	100	80	91.3	90.9	100
Oral Corticosteroid Use: Yes -ACR70(n=2,5,23,33,3)	100	80	82.6	84.8	100
Oral Corticosteroid Use: Yes -ACR90(n=2,5,23,33,3)	100	80	65.2	69.7	66.7
Oral Corticosteroid Use: No -ACR30(n=7,6,32,49,4)	100	100	96.9	98	100
Oral Corticosteroid Use: No -ACR50(n=7,6,32,49,4)	100	100	84.4	89.8	100
Oral Corticosteroid Use: No -ACR70(n=7,6,32,49,4)	85.7	100	84.4	87.8	100
Oral Corticosteroid Use: No -ACR90(n=7,6,32,49,4)	85.7	66.7	68.8	71.4	75
Rheumatoid Factor: Positive - ACR30(n=0,2,23,27,2)	0	100	95.7	96.3	100
Rheumatoid Factor: Positive - ACR50(n=0,2,23,27,2)	0	100	91.3	92.6	100
Rheumatoid Factor: Positive - ACR70(n=0,2,23,27,2)	0	100	91.3	92.6	100
Rheumatoid Factor: Positive - ACR90(n=0,2,23,27,2)	0	100	78.3	77.8	50
Rheumatoid Factor: Negative - ACR30(n=9,7,29,50,5)	100	100	93.1	96	100
Rheumatoid Factor: Negative - ACR50(n=9,7,29,50,5)	100	100	82.8	90	100
Rheumatoid Factor: Negative - ACR70(n=9,7,29,50,5)	88.9	100	75.9	84	100
Rheumatoid Factor: Negative - ACR90(n=9,7,29,50,5)	88.9	85.7	58.6	70	80

No statistical analyses for this end point

Secondary: Change From Baseline in the Juvenile Arthritis Disease Activity Score-71 (JADAS-71) at Week 104

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End point title

Change From Baseline in the Juvenile Arthritis Disease Activity Score-71 (JADAS-71) at Week 104

End point description

The JADAS-71 is composed of 4 components: Physician global assessment of disease activity on a visual analog scale (VAS) (range = 0-10, left end of the line = arthritis inactive, ie, symptom-free and no arthritis symptoms; right end = arthritis very active), patient/parent global assessment of overall well-being on a VAS (range = 0-10, left end of the line = very well, ie, symptom-free and no arthritis disease activity; right end = very poor, ie, maximum arthritis disease activity), normalized erythrocyte sedimentation rate (ESR) (range = 0-10, If ESR is ≤ 20 mm/h, set to 0. If ≥ 120 mm/h, set to 10 mm/h. If > 20 mm/h and < 120 mm/h, apply formula: [ESR − 20 mm/h]/10 mm/h), and a count of active arthritis (swelling present or pain present and limitation of motion) in 71 selected joints (range=0-71). The JADAS-71 is the sum of the 4 component scores and ranges from 0-101. A higher score indicates more arthritis disease activity. A positive change score indicates improvement.

End point type

Secondary

End point timeframe

Baseline to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	7	11	51	76	7
Units: Units on a scale
arithmetic mean (standard deviation)	-31.4 ( 17.471 )	-25.42 ( 13.142 )	-25.7 ( 12.2 )	-26.05 ( 12.941 )	-24.17 ( 14.856 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at Week 104

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End point title

Percent Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at Week 104

End point description

End point type

Secondary

End point timeframe

Baseline to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	7	11	51	76	7
Units: Percent change
arithmetic mean (standard deviation)	-97.65 ( 2.689 )	-90.42 ( 16.306 )	-87.58 ( 27.588 )	-89.7 ( 23.747 )	-96.01 ( 9.862 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at Week 104

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End point title

Percent Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at Week 104

End point description

End point type

Secondary

End point timeframe

Baseline to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	7	11	51	76	7
Units: Percent change
arithmetic mean (standard deviation)	-97.01 ( 5.323 )	-83.06 ( 25.986 )	-75.81 ( 42.143 )	-75.35 ( 43.779 )	-38.23 ( 75.749 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline the JIA ACR Component Score Number of Joints With Active Arthritis at Week 104

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End point title

Percent Change From Baseline the JIA ACR Component Score Number of Joints With Active Arthritis at Week 104

End point description

End point type

Secondary

End point timeframe

Baseline to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	7	11	52	77	7
Units: Percent change
arithmetic mean (standard deviation)	-98.57 ( 3.78 )	-76.43 ( 44.956 )	-88.6 ( 24.043 )	-87.73 ( 27.088 )	-88.22 ( 24.908 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at Week 104

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End point title

Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at Week 104

End point description

End point type

Secondary

End point timeframe

Baseline to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	7	11	52	77	7
Units: Percent change
arithmetic mean (standard deviation)	-98.57 ( 3.78 )	-76.66 ( 55.781 )	-79.88 ( 26.831 )	-81.3 ( 31.729 )	-81.81 ( 32.048 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the JIA ACR Component Score ESR at Week 104 [ Time Frame: Baseline to Week 104 ]

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End point title

Percent Change From Baseline in the JIA ACR Component Score ESR at Week 104 [ Time Frame: Baseline to Week 104 ]

End point description

Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory. A negative change score indicates improvement.

End point type

Secondary

End point timeframe

Baseline to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	7	11	52	77	7
Units: Percent change
arithmetic mean (standard deviation)	-84.42 ( 13.141 )	-74.06 ( 31.967 )	-73.85 ( 29.073 )	-76.24 ( 27.263 )	-89.21 ( 4.682 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the JIA ACR Component Score Functional Ability at Week 104 [ Time Frame: Baseline to Week 104 ]

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End point title

Percent Change From Baseline in the JIA ACR Component Score Functional Ability at Week 104 [ Time Frame: Baseline to Week 104 ]

End point description

Functional ability is assessed with the Childhood Health Assessment Questionnaire (CHAQ-DI) disability index which consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. If aids and devices listed in the questionnaire or assistance from a person are required to perform a task, a domain score of 0 or 1 is increased to 2; if the domain score is 2 or 3, the domain score is not adjusted. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A negative change score indicates improvement.

End point type

Secondary

End point timeframe

Baseline to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	7	11	52	77	7
Units: Percent change
arithmetic mean (standard deviation)	-96.03 ( 10.499 )	-78.58 ( 38.745 )	-73.34 ( 38.745 )	-76.71 ( 34.696 )	-79.5 ( 18.622 )

No statistical analyses for this end point

Secondary: Percent of Patients With a Minimally Important Improvement in the CHAQ-DI Score at Weeks 16, 40, 52, 80, and 104

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End point title

Percent of Patients With a Minimally Important Improvement in the CHAQ-DI Score at Weeks 16, 40, 52, 80, and 104

End point description

The CHAQ-DI consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. If aids and devices listed in the questionnaire or assistance from a person are required to perform a task, a domain score of 0 or 1 is increased to 2; if the domain score is 2 or 3, the domain score is not adjusted. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A minimally important improvement is an improvement ≥ 0.13 over Baseline. Patients who withdrew due to non-safety reasons are classified as non-responders.

End point type

Secondary

End point timeframe

Baseline to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	9	11	55	82	7
Units: Percent of patients
number (not applicable)
Week 16	77.8	81.8	76.4	78	85.7
Week 40	88.9	81.8	78.2	81.7	100
Week 52	88.9	81.8	80	82.9	100
Week 80	88.9	90.9	80	84.1	100
Week 104	88.9	100	80	85.4	100

No statistical analyses for this end point

Secondary: C-reactive Protein Levels From Baseline to Week 104

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End point title

C-reactive Protein Levels From Baseline to Week 104

End point description

C-reactive protein (CRP), an acute phase protein, was measured in blood samples with a high-sensitivity CRP (hs-CRP) test using laser nephelometry.

End point type

Secondary

End point timeframe

Baseline to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	9	9	53	78	7
Units: mg/L
arithmetic mean (standard deviation)
Week 16 (n=9, 7, 53, 75, 6)	1.726 ( 2.7395 )	1.077 ( 1.1247 )	1.137 ( 3.2472 )	1.129 ( 2.9042 )	0.22 ( 0.04 )
Week 40 (n=7, 11, 51, 76, 7)	3.709 ( 9.0383 )	1.591 ( 2.6187 )	1.451 ( 5.9168 )	1.756 ( 5.8029 )	2.286 ( 5.5183 )
Week 52 (n=8, 10, 52, 77, 7)	3.405 ( 8.6491 )	4.584 ( 10.4573 )	0.882 ( 2.4335 )	1.569 ( 5.0838 )	0.267 ( 0.1325 )
Week 80 (n=8, 10, 51, 76, 7)	2.329 ( 5.9286 )	4.867 ( 13.0151 )	0.718 ( 1.5474 )	1.425 ( 5.225 )	0.623 ( 0.6096 )
Week 104 (n=7, 11, 50, 75, 7)	0.249 ( 0.0949 )	1.259 ( 2.8519 )	2.032 ( 6.5732 )	1.581 ( 5.4965 )	0.2 ( 0 )

No statistical analyses for this end point

Secondary: Change From Baseline in the Pain VAS Score at Weeks 2, 40, 52, and 104

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End point title

Change From Baseline in the Pain VAS Score at Weeks 2, 40, 52, and 104

End point description

End point type

Secondary

End point timeframe

Baseline to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	9	11	55	82	7
Units: Units on a scale
arithmetic mean (standard deviation)
Week 2 (n=9, 10, 52, 78, 7)	-11.4 ( 13.16 )	-6.1 ( 20.98 )	-10.3 ( 21.44 )	-9.4 ( 19.8 )	-4.4 ( 13.13 )
Week 40 (n=8, 11, 52, 78, 7)	-44 ( 12.29 )	-27.9 ( 35.85 )	-33.9 ( 31.64 )	-33.3 ( 30.44 )	-24.7 ( 27.76 )
Week 52 (n=8, 1, 52, 78, 7)	-47.8 ( 14.46 )	-29.6 ( 28.39 )	-35.5 ( 29.07 )	-34.9 ( 27.76 )	-24 ( 26.59 )
Week 104 (n=7, 11, 51, 76, 7)	-48.9 ( 16.71 )	-27.1 ( 39.51 )	-34.5 ( 34.59 )	-34.4 ( 33.72 )	-30.7 ( 31.63 )

No statistical analyses for this end point

Secondary: Percent of Patients With Inactive Disease From Week 16 to Week 104

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End point title

Percent of Patients With Inactive Disease From Week 16 to Week 104 ^[13]

End point description

End point type

Secondary

End point timeframe

Week 16 to Week 104

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg	All Tocilizumab Patients
Number of subjects analysed	9	11	55	7	82
Units: Percent of patients
number (not applicable)
Week 16	11.1	18.2	20	42.9	20.7
Week 40	44.4	45.5	38.2	42.9	40.2
Week 52	66.7	45.5	50.9	57.1	52.4
Week 80	66.7	54.5	56.4	57.1	57.3
Week 104	66.7	54.5	63.6	71.4	63.4

No statistical analyses for this end point

Secondary: Percent of Patients in Clinical Remission From Week 40 to 104

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End point title

Percent of Patients in Clinical Remission From Week 40 to 104 ^[14]

End point description

A patient was in clinical remission if they had inactive disease at all visits in the 6 months prior to and including the visit assessment day. A patient was judged to have inactive disease if all of the following criteria were met: Number of joints with active arthritis = 0; absence of active uveitis, defined by the adverse event preferred terms ‘uveitis’ and ‘intermediate uveitis’; normal erythrocyte sedimentation rate (< 20 mm/hour regardless of age and sex); and physician’s global assessment of overall well-being visual analog scale score ≤ 10. Patients who withdrew due to non-safety reasons are classified as non-responders.

End point type

Secondary

End point timeframe

Week 40 to Week 104

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg	All Tocilizumab Patients
Number of subjects analysed	9	11	55	7	82
Units: Percent of patients
number (not applicable)
Week 40	0	0	7.3	14.3	6.1
Week 52	22.2	18.2	18.2	14.3	18.3
Week 80	55.6	36.4	25.5	42.9	31.7
Week 104	55.6	27.3	34.5	57.1	37.8

No statistical analyses for this end point

Secondary: Percent of Patients Achieving JIA ACR30/50/70/90 Responses at Week 104 by Duration of Disease (< 2 Years, ≥ 2 Years)

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End point title

Percent of Patients Achieving JIA ACR30/50/70/90 Responses at Week 104 by Duration of Disease (< 2 Years, ≥ 2 Years) ^[15]

End point description

A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]). Patients who withdrew due to non-safety reasons are classified as non-responders.

End point type

Secondary

End point timeframe

Baseline to Week 104

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg	All Tocilizumab Patients
Number of subjects analysed	9	11	55	7	82
Units: Percent of patients
number (not applicable)
Disease Duration < 2 Years - ACR30 (n=4,4,17,1,26)	100	100	88.2	100	92.3
Disease Duration < 2 Years - ACR50 (n=4,4,17,1,26)	100	100	82.4	100	88.5
Disease Duration < 2 Years - ACR70 (n=4,4,17,1,26)	100	100	82.4	100	88.5
Disease Duration < 2 Years - ACR90 (n=4,4,17,1,26)	100	100	76.5	100	84.6
Disease Duration ≥ 2 Years - ACR30 (n=5,7,38,6,56)	100	85.7	97.4	100	96.4
Disease Duration ≥ 2 Years - ACR50 (n=5,7,38,6,56)	100	85.7	89.5	100	91.1
Disease Duration ≥ 2 Years - ACR70 (n=5,7,38,6,56)	80	85.7	84.2	100	85.7
Disease Duration ≥ 2 Years - ACR90 (n=5,7,38,6,56)	80	57.1	63.2	66.7	64.3

No statistical analyses for this end point

Secondary: Oral Corticosteroid Dose at Baseline, Week 52, and Week 104

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End point title

Oral Corticosteroid Dose at Baseline, Week 52, and Week 104 ^[16]

End point description

Due to the different types of corticosteroid medications available, the prednisone equivalent was used in the calculation of the oral corticosteroid dose. Values are based on the average daily dose on the study day and if not available the last observation carried forward is used.

End point type

Secondary

End point timeframe

Baseline to Week 104

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Participants	Tocilizumab 10mg/kg to 8 mg/kg in Patients weighing <30kg
Number of subjects analysed	22	34	119	188	13
Units: mg/kg/day
arithmetic mean (standard deviation)
Baseline (n=22, 34, 119, 188, 13)	0.041 ( 0.0704 )	0.079 ( 0.0802 )	0.055 ( 0.0708 )	0.061 ( 0.0743 )	0.095 ( 0.0836 )
Week 52 (n=17, 24, 105, 159, 13)	0.021 ( 0.0474 )	0.037 ( 0.0591 )	0.032 ( 0.049 )	0.034 ( 0.0518 )	0.064 ( 0.0599 )
Week 104 (n=16, 23, 103, 155, 13)	0.014 ( 0.0418 )	0.019 ( 0.0412 )	0.02 ( 0.0558 )	0.02 ( 0.0518 )	0.028 ( 0.0497 )

No statistical analyses for this end point

Secondary: Methotrexate Dose at Baseline, Week 52, and Week 104

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End point title

Methotrexate Dose at Baseline, Week 52, and Week 104

End point description

Values are based on the average daily dose on the study day and if not available the last observation carried forward is used.

End point type

Secondary

End point timeframe

Baseline to Week 104

End point values	Tocilizumab 10 mg/kg in Patients Weighing <30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	Tocilizumab 8 or 10 mg/kg	All Tocilizumab Participants
Number of subjects analysed	22	34	119	13	188
Units: mg/m^2/week
arithmetic mean (standard deviation)
Baseline (n=22, 34, 118, 13, 187)	11.304 ( 6.7521 )	12.146 ( 5.2822 )	8.768 ( 5.5387 )	17.562 ( 17.0864 )	10.292 ( 7.3586 )
Week 52 (n=17, 24, 105, 13, 159)	9.247 ( 5.6513 )	11.216 ( 4.689 )	8.326 ( 4.9825 )	15.568 ( 15.2521 )	9.453 ( 6.6963 )
Week 104 (n=16, 23, 103, 13, 155)	8.342 ( 5.2618 )	10.05 ( 4.6316 )	6.855 ( 5.0401 )	11.858 ( 14.3458 )	7.902 ( 6.4332 )

No statistical analyses for this end point

Secondary: Height Standard Deviation Score at Baseline, Week 52, and Week 104

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End point title

Height Standard Deviation Score at Baseline, Week 52, and Week 104 ^[17]

End point description

The height Standard Deviation Score was calculated using the following formula: (Observed height - median of the reference population)/standard deviation of the reference population. The reference population was defined as that of the same sex and age to the nearest completed year and month using the World Health Organization norms. A negative score indicates less height than the reference population.

End point type

Secondary

End point timeframe

Baseline to Week 104

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: This endpoint data were not analyzed for all baseline period arms.

End point values	Placebo	Tocilizumab 8 or 10 mg/kg	All Tocilizumab Participants
Number of subjects analysed	84	82	187
Units: Standard deviation score
arithmetic mean (standard deviation)
Baseline	-0.57 ( 1.005 )	-0.33 ( 1.29 )	-0.51 ( 1.219 )
Week 52	-0.51 ( 1.004 )	-0.15 ( 1.216 )	-0.33 ( 1.125 )
Week 104	-0.34 ( 0.954 )	-0.01 ( 1.15 )	-0.18 ( 1.066 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All exposure safety population: All participants randomized into Part I of the study who received at least 1 infusion of tocilizumab and had at least 1 post-baseline safety assessment or event.

Adverse event reporting additional description

The patients were exposed to weight adjusted doses for the 104 week duration of the study with the exception of those patients randomized in Part II (Weeks 16-40) to receive placebo. Adverse events (AE) are reported for all participants and by the various weight-based dose groups. AEs which occurred in the placebo group in Part II are not included.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

14.1

Reporting group title

Tocilizumab 10 mg/kg in Patients Weighing < 30 kg

Reporting group description

Reporting group title

Tocilizumab 10 mg/kg to 8 mg/kg in Patients Weighing < 30 kg

Reporting group description

Reporting group title

Tocilizumab 8 mg/kg in Patients Weighing < 30 kg

Reporting group description

Reporting group title

Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg

Reporting group description

Reporting group title

All Tocilizumab Patients

Reporting group description

Serious adverse events	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 10 mg/kg to 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 22 (18.18%)	1 / 13 (7.69%)	4 / 34 (11.76%)	17 / 119 (14.29%)	26 / 188 (13.83%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Injury, poisoning and procedural complications
Neck injury
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Synovial rupture
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Familial mediterranean fever
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Benign intracranial hypertension
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Pregnancy
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Uveitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	2 / 34 (5.88%)	0 / 119 (0.00%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis sclerosing
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertransaminasaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthmatic crisis
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Psychosomatic disease
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus urinary
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoporosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Scleroderma
subjects affected / exposed	1 / 22 (4.55%)	0 / 13 (0.00%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 22 (4.55%)	0 / 13 (0.00%)	0 / 34 (0.00%)	3 / 119 (2.52%)	4 / 188 (2.13%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 3	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 22 (9.09%)	0 / 13 (0.00%)	1 / 34 (2.94%)	0 / 119 (0.00%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	2 / 119 (1.68%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varicella
subjects affected / exposed	1 / 22 (4.55%)	0 / 13 (0.00%)	1 / 34 (2.94%)	0 / 119 (0.00%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epstein-Barr Virus Infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paronychia
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	1 / 34 (2.94%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	1 / 34 (2.94%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Tocilizumab 10 mg/kg in Patients Weighing < 30 kg	Tocilizumab 10 mg/kg to 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing < 30 kg	Tocilizumab 8 mg/kg in Patients Weighing ≥ 30 kg	All Tocilizumab Patients
Total subjects affected by non serious adverse events
subjects affected / exposed	19 / 22 (86.36%)	11 / 13 (84.62%)	25 / 34 (73.53%)	102 / 119 (85.71%)	157 / 188 (83.51%)
Vascular disorders
Hypotension
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	1 / 34 (2.94%)	2 / 119 (1.68%)	4 / 188 (2.13%)
occurrences all number	0	2	1	2	5
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	2 / 34 (5.88%)	4 / 119 (3.36%)	7 / 188 (3.72%)
occurrences all number	0	1	3	5	9
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences all number	0	1	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 22 (18.18%)	2 / 13 (15.38%)	6 / 34 (17.65%)	13 / 119 (10.92%)	25 / 188 (13.30%)
occurrences all number	4	3	9	16	32
Oropharyngeal pain
subjects affected / exposed	1 / 22 (4.55%)	0 / 13 (0.00%)	3 / 34 (8.82%)	15 / 119 (12.61%)	19 / 188 (10.11%)
occurrences all number	1	0	7	20	28
Epistaxis
subjects affected / exposed	2 / 22 (9.09%)	0 / 13 (0.00%)	1 / 34 (2.94%)	5 / 119 (4.20%)	8 / 188 (4.26%)
occurrences all number	3	0	1	5	9
Rhinorrhoea
subjects affected / exposed	1 / 22 (4.55%)	1 / 13 (7.69%)	0 / 34 (0.00%)	4 / 119 (3.36%)	6 / 188 (3.19%)
occurrences all number	1	1	0	4	6
Pneumonitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	2 / 34 (5.88%)	1 / 119 (0.84%)	3 / 188 (1.60%)
occurrences all number	0	0	2	1	3
Nasal obstruction
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	1 / 34 (2.94%)	0 / 119 (0.00%)	2 / 188 (1.06%)
occurrences all number	0	1	1	0	2
Productive cough
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	1 / 119 (0.84%)	2 / 188 (1.06%)
occurrences all number	0	1	0	1	2
Rhinitis allergic
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences all number	0	1	0	0	1
Sneezing
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences all number	0	1	0	0	1
Investigations
Transaminases increased
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	4 / 119 (3.36%)	5 / 188 (2.66%)
occurrences all number	0	1	0	4	5
Injury, poisoning and procedural complications
Ligament sprain
subjects affected / exposed	2 / 22 (9.09%)	1 / 13 (7.69%)	1 / 34 (2.94%)	3 / 119 (2.52%)	7 / 188 (3.72%)
occurrences all number	2	1	1	4	8
Arthropod bite
subjects affected / exposed	2 / 22 (9.09%)	1 / 13 (7.69%)	1 / 34 (2.94%)	2 / 119 (1.68%)	6 / 188 (3.19%)
occurrences all number	3	1	1	2	7
Contusion
subjects affected / exposed	2 / 22 (9.09%)	0 / 13 (0.00%)	0 / 34 (0.00%)	2 / 119 (1.68%)	4 / 188 (2.13%)
occurrences all number	2	0	0	2	4
Thermal burn
subjects affected / exposed	1 / 22 (4.55%)	1 / 13 (7.69%)	2 / 34 (5.88%)	0 / 119 (0.00%)	4 / 188 (2.13%)
occurrences all number	1	1	2	0	4
Fall
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	1 / 34 (2.94%)	1 / 119 (0.84%)	3 / 188 (1.60%)
occurrences all number	0	1	1	1	3
Tibia fracture
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	2 / 119 (1.68%)	3 / 188 (1.60%)
occurrences all number	0	1	0	2	3
Foot fracture
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	1 / 119 (0.84%)	2 / 188 (1.06%)
occurrences all number	0	1	0	1	2
Nervous system disorders
Headache
subjects affected / exposed	1 / 22 (4.55%)	3 / 13 (23.08%)	5 / 34 (14.71%)	22 / 119 (18.49%)	31 / 188 (16.49%)
occurrences all number	1	4	6	41	52
Dizziness
subjects affected / exposed	1 / 22 (4.55%)	0 / 13 (0.00%)	0 / 34 (0.00%)	7 / 119 (5.88%)	8 / 188 (4.26%)
occurrences all number	1	0	0	11	12
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	1 / 119 (0.84%)	2 / 188 (1.06%)
occurrences all number	0	3	0	1	4
Eosinophilia
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences all number	0	1	0	0	1
Hypochromic anaemia
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences all number	0	1	0	0	1
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	2 / 34 (5.88%)	6 / 119 (5.04%)	8 / 188 (4.26%)
occurrences all number	0	0	2	6	8
Eye disorders
Conjunctivitis
subjects affected / exposed	2 / 22 (9.09%)	0 / 13 (0.00%)	1 / 34 (2.94%)	6 / 119 (5.04%)	9 / 188 (4.79%)
occurrences all number	2	0	1	6	9
Iridocyclitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	2 / 34 (5.88%)	0 / 119 (0.00%)	2 / 188 (1.06%)
occurrences all number	0	0	2	0	2
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	2 / 34 (5.88%)	15 / 119 (12.61%)	17 / 188 (9.04%)
occurrences all number	0	0	2	26	28
Diarrhoea
subjects affected / exposed	1 / 22 (4.55%)	0 / 13 (0.00%)	2 / 34 (5.88%)	14 / 119 (11.76%)	17 / 188 (9.04%)
occurrences all number	1	0	2	16	19
Vomiting
subjects affected / exposed	1 / 22 (4.55%)	1 / 13 (7.69%)	3 / 34 (8.82%)	12 / 119 (10.08%)	17 / 188 (9.04%)
occurrences all number	1	1	4	14	20
Abdominal pain
subjects affected / exposed	1 / 22 (4.55%)	1 / 13 (7.69%)	2 / 34 (5.88%)	12 / 119 (10.08%)	16 / 188 (8.51%)
occurrences all number	1	1	2	18	22
Abdominal pain upper
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	2 / 34 (5.88%)	8 / 119 (6.72%)	10 / 188 (5.32%)
occurrences all number	0	0	5	9	14
Mouth ulceration
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	1 / 34 (2.94%)	6 / 119 (5.04%)	7 / 188 (3.72%)
occurrences all number	0	0	1	11	12
Aphthous stomatitis
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	1 / 34 (2.94%)	3 / 119 (2.52%)	5 / 188 (2.66%)
occurrences all number	0	1	1	5	7
Dental caries
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	3 / 119 (2.52%)	4 / 188 (2.13%)
occurrences all number	0	1	0	3	4
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 22 (4.55%)	0 / 13 (0.00%)	3 / 34 (8.82%)	7 / 119 (5.88%)	11 / 188 (5.85%)
occurrences all number	1	0	4	8	13
Ingrowing nail
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	0 / 34 (0.00%)	6 / 119 (5.04%)	6 / 188 (3.19%)
occurrences all number	0	0	0	7	7
Urticaria
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	5 / 119 (4.20%)	6 / 188 (3.19%)
occurrences all number	0	1	0	7	8
Eczema
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	2 / 34 (5.88%)	3 / 119 (2.52%)	5 / 188 (2.66%)
occurrences all number	0	0	2	4	6
Alopecia
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	2 / 34 (5.88%)	1 / 119 (0.84%)	3 / 188 (1.60%)
occurrences all number	0	0	2	1	3
Erythema
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	1 / 34 (2.94%)	1 / 119 (0.84%)	3 / 188 (1.60%)
occurrences all number	0	1	1	1	3
Prurigo
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	2 / 34 (5.88%)	0 / 119 (0.00%)	2 / 188 (1.06%)
occurrences all number	0	0	3	0	3
Musculoskeletal and connective tissue disorders
Juvenile arthritis
subjects affected / exposed	6 / 22 (27.27%)	3 / 13 (23.08%)	6 / 34 (17.65%)	37 / 119 (31.09%)	52 / 188 (27.66%)
occurrences all number	6	3	7	49	65
Arthralgia
subjects affected / exposed	3 / 22 (13.64%)	2 / 13 (15.38%)	0 / 34 (0.00%)	5 / 119 (4.20%)	10 / 188 (5.32%)
occurrences all number	3	5	0	7	15
Muscle disorder
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences all number	0	1	0	0	1
Polyarthritis
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences all number	0	1	0	0	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	7 / 22 (31.82%)	1 / 13 (7.69%)	5 / 34 (14.71%)	32 / 119 (26.89%)	45 / 188 (23.94%)
occurrences all number	11	1	15	57	84
Upper respiratory tract infection
subjects affected / exposed	2 / 22 (9.09%)	0 / 13 (0.00%)	4 / 34 (11.76%)	17 / 119 (14.29%)	23 / 188 (12.23%)
occurrences all number	6	0	4	37	47
Pharyngitis
subjects affected / exposed	4 / 22 (18.18%)	1 / 13 (7.69%)	3 / 34 (8.82%)	18 / 119 (15.13%)	26 / 188 (13.83%)
occurrences all number	7	2	4	23	36
Rhinitis
subjects affected / exposed	1 / 22 (4.55%)	2 / 13 (15.38%)	5 / 34 (14.71%)	7 / 119 (5.88%)	15 / 188 (7.98%)
occurrences all number	2	2	8	7	19
Ear infection
subjects affected / exposed	1 / 22 (4.55%)	2 / 13 (15.38%)	2 / 34 (5.88%)	10 / 119 (8.40%)	15 / 188 (7.98%)
occurrences all number	1	3	3	14	21
Gastroenteritis
subjects affected / exposed	1 / 22 (4.55%)	0 / 13 (0.00%)	3 / 34 (8.82%)	7 / 119 (5.88%)	11 / 188 (5.85%)
occurrences all number	2	0	4	11	17
Influenza
subjects affected / exposed	2 / 22 (9.09%)	1 / 13 (7.69%)	1 / 34 (2.94%)	7 / 119 (5.88%)	11 / 188 (5.85%)
occurrences all number	3	1	1	8	13
Sinusitis
subjects affected / exposed	1 / 22 (4.55%)	2 / 13 (15.38%)	2 / 34 (5.88%)	5 / 119 (4.20%)	10 / 188 (5.32%)
occurrences all number	1	2	2	5	10
Bronchitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 13 (0.00%)	1 / 34 (2.94%)	6 / 119 (5.04%)	8 / 188 (4.26%)
occurrences all number	2	0	1	8	11
Urinary tract infection
subjects affected / exposed	1 / 22 (4.55%)	0 / 13 (0.00%)	1 / 34 (2.94%)	6 / 119 (5.04%)	8 / 188 (4.26%)
occurrences all number	1	0	1	6	8
Oral herpes
subjects affected / exposed	2 / 22 (9.09%)	1 / 13 (7.69%)	1 / 34 (2.94%)	3 / 119 (2.52%)	7 / 188 (3.72%)
occurrences all number	3	1	1	3	8
Pharyngotonsillitis
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	6 / 119 (5.04%)	7 / 188 (3.72%)
occurrences all number	0	1	0	8	9
Otitis media
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	2 / 34 (5.88%)	3 / 119 (2.52%)	5 / 188 (2.66%)
occurrences all number	0	0	4	3	7
Pneumonia
subjects affected / exposed	2 / 22 (9.09%)	0 / 13 (0.00%)	0 / 34 (0.00%)	3 / 119 (2.52%)	5 / 188 (2.66%)
occurrences all number	2	0	0	3	5
Respiratory tract infection viral
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	4 / 119 (3.36%)	5 / 188 (2.66%)
occurrences all number	0	1	0	6	7
Viral infection
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	1 / 34 (2.94%)	3 / 119 (2.52%)	4 / 188 (2.13%)
occurrences all number	0	1	1	3	4
Laryngitis
subjects affected / exposed	2 / 22 (9.09%)	0 / 13 (0.00%)	0 / 34 (0.00%)	1 / 119 (0.84%)	3 / 188 (1.60%)
occurrences all number	2	0	0	1	3
Varicella
subjects affected / exposed	1 / 22 (4.55%)	2 / 13 (15.38%)	0 / 34 (0.00%)	0 / 119 (0.00%)	5 / 188 (2.66%)
occurrences all number	1	2	0	0	5
Infection parasitic
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	1 / 34 (2.94%)	0 / 119 (0.00%)	2 / 188 (1.06%)
occurrences all number	0	1	1	0	2
Mumps
subjects affected / exposed	0 / 22 (0.00%)	0 / 13 (0.00%)	2 / 34 (5.88%)	0 / 119 (0.00%)	2 / 188 (1.06%)
occurrences all number	0	0	2	0	2
Abscess
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences all number	0	1	0	0	1
Skin bacterial infection
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences all number	0	1	0	0	1
Respiratory tract infection
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	1 / 34 (2.94%)	2 / 119 (1.68%)	4 / 188 (2.13%)
occurrences all number	0	1	1	2	4
Abscess limb
subjects affected / exposed	0 / 22 (0.00%)	1 / 13 (7.69%)	0 / 34 (0.00%)	0 / 119 (0.00%)	1 / 188 (0.53%)
occurrences all number	0	1	0	0	1

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A 24-Week Randomized Double-Blind, Placebo Controlled Withdrawal Trial With a 16-Week Open-Label Lead-In Phase, and 64-Week Open-Label Follow-Up, to Evaluate the Efficacy and Safety of Tocilizumab in Patients with Active Polyarticular Juvenile Idiopathic Arthritis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent of Patients With a Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology 30 (ACR30) Flare in Part II of the Study (Weeks 16-40)

Primary: Percent of Patients With a Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology 30 (ACR30) Flare in Part II of the Study (Weeks 16-40)

Secondary: Percent of Patients Achieving JIA ACR30/50/70/90 Responses in Part I of the Study (Baseline to Week 16)

Secondary: Percent of Patients Achieving JIA ACR30/50/70/90 Responses in Part I of the Study (Baseline to Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at the End of Part I of the Study (Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at the End of Part I of the Study (Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at the End of Part I of the Study (Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at the End of Part I of the Study (Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Active Arthritis at the End of Part I of the Study (Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Active Arthritis at the End of Part I of the Study (Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at the End of Part I of the Study (Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at the End of Part I of the Study (Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score ESR at the End of Part I of the Study (Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score ESR at the End of Part I of the Study (Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score Functional Ability at the End of Part I of the Study (Week 16)

Secondary: Percent Change From Baseline in the JIA ACR Component Score Functional Ability at the End of Part I of the Study (Week 16)

Secondary: Juvenile Arthritis Disease Activity Score (JADAS-27) at the End of Part I of the Study (Week 16)

Secondary: Juvenile Arthritis Disease Activity Score (JADAS-27) at the End of Part I of the Study (Week 16)

Secondary: Pain Visual Analogue Scale (VAS) Score at the End of Part I of the Study (Week 16)

Secondary: Pain Visual Analogue Scale (VAS) Score at the End of Part I of the Study (Week 16)

Secondary: Percentage of Patients With Inactive Disease at the End of Part I of the Study (Week 16)

Secondary: Percentage of Patients With Inactive Disease at the End of Part I of the Study (Week 16)

Secondary: Percentage of Patients With an Elevated C-reactive Protein Concentration at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

Secondary: Percentage of Patients With an Elevated C-reactive Protein Concentration at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

Secondary: Percentage of Patients With an Elevated ESR at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

Secondary: Percentage of Patients With an Elevated ESR at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

Secondary: Percentage of Patients With an Elevated Platelet Count at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

Secondary: Percentage of Patients With an Elevated Platelet Count at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

Secondary: Percentage of Patients With an Elevated White Blood Count at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

Secondary: Percentage of Patients With an Elevated White Blood Count at Baseline That Had Normalized at the End of Part I of the Study (Week 16)

Secondary: Percent of Patients Achieving JIA ACR30/50/70/90 Responses at the End of Part II of the Study (Week 40)

Secondary: Percent of Patients Achieving JIA ACR30/50/70/90 Responses at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score Number of Joints With Active Arthritis at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score Number of Joints With Active Arthritis at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score ESR at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score ESR at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score CHAQ-DI at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the JIA ACR Component Score CHAQ-DI at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the Pain VAS Score at the End of Part II of the Study (Week 40)

Secondary: Change From Baseline in the Pain VAS Score at the End of Part II of the Study (Week 40)

Secondary: Percent of Patients With Inactive Disease at the End of Part II of the Study (Week 40)

Secondary: Percent of Patients With Inactive Disease at the End of Part II of the Study (Week 40)

Secondary: Percent of Patients Achieving JIA ACR30/50/70/90 Responses at Weeks 2, 52, and 104

Secondary: Percent of Patients Achieving JIA ACR30/50/70/90 Responses at Weeks 2, 52, and 104

Secondary: Percent of Patients With 4 Baseline Disease Characteristics Achieving JIA ACR30/50/70/90 Responses at Week 104

Secondary: Percent of Patients With 4 Baseline Disease Characteristics Achieving JIA ACR30/50/70/90 Responses at Week 104

Secondary: Change From Baseline in the Juvenile Arthritis Disease Activity Score-71 (JADAS-71) at Week 104

Secondary: Change From Baseline in the Juvenile Arthritis Disease Activity Score-71 (JADAS-71) at Week 104

Secondary: Percent Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at Week 104

Secondary: Percent Change From Baseline in the JIA ACR Component Score Physician Global Assessment of Disease Activity at Week 104

Secondary: Percent Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at Week 104

Secondary: Percent Change From Baseline in the JIA ACR Component Score Patient/Parent Global Assessment of Overall Well-being at Week 104

Secondary: Percent Change From Baseline the JIA ACR Component Score Number of Joints With Active Arthritis at Week 104

Secondary: Percent Change From Baseline the JIA ACR Component Score Number of Joints With Active Arthritis at Week 104

Secondary: Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at Week 104

Secondary: Percent Change From Baseline in the JIA ACR Component Score Number of Joints With Limitation of Movement at Week 104

Secondary: Percent Change From Baseline in the JIA ACR Component Score ESR at Week 104 [ Time Frame: Baseline to Week 104 ]

Secondary: Percent Change From Baseline in the JIA ACR Component Score ESR at Week 104 [ Time Frame: Baseline to Week 104 ]

Secondary: Percent Change From Baseline in the JIA ACR Component Score Functional Ability at Week 104 [ Time Frame: Baseline to Week 104 ]

Secondary: Percent Change From Baseline in the JIA ACR Component Score Functional Ability at Week 104 [ Time Frame: Baseline to Week 104 ]

Secondary: Percent of Patients With a Minimally Important Improvement in the CHAQ-DI Score at Weeks 16, 40, 52, 80, and 104

Secondary: Percent of Patients With a Minimally Important Improvement in the CHAQ-DI Score at Weeks 16, 40, 52, 80, and 104

Secondary: C-reactive Protein Levels From Baseline to Week 104

Secondary: C-reactive Protein Levels From Baseline to Week 104

Clinical Trial Results:
A 24-Week Randomized Double-Blind, Placebo Controlled Withdrawal Trial With a 16-Week Open-Label Lead-In Phase, and 64-Week Open-Label Follow-Up, to Evaluate the Efficacy and Safety of Tocilizumab in Patients with Active Polyarticular Juvenile Idiopathic Arthritis