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    Clinical Trial Results:
    A PHASE Ib, OPEN-LABEL, MULTICENTER STUDY TO INVESTIGATE THE PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF TOCILIZUMAB FOLLOWING SUBCUTANEOUS ADMINISTRATION TO PATIENTS WITH SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS

    Summary
    EudraCT number
    		 2012-003490-26
    Trial protocol
    		 DE   IT   GB   ES   Outside EU/EEA  
    Global end of trial date
    13 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Dec 2017
    First version publication date
    24 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WA28118
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01904292
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    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
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the pharmacokinetics, pharmacodynamics, and safety of subcutaneously administered tocilizumab in participants with Systemic Juvenile Idiopathic Arthritis (sJIA)
    Protection of trial subjects
    This study will be conducted in full conformance with the ICH E6 guideline for GCP and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    51
    EEA total number of subjects
    25
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    3
    Children (2-11 years)
    28
    Adolescents (12-17 years)
    20
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were assigned to one of two dosing regimens based on the following BW criteria: patients weighing < 30 kg received 162 mg of TCZ SC Q10D or TCZ SC Q2W for 52 weeks. Patients weighing > 30 kg received 162 mg of TCZ SC QW for 52 weeks.

    Pre-assignment
    Screening details
    		 Screening tests and evaluations were performed within 21 days prior to baseline. All screening evaluations had to be completed and reviewed to confirm that patients met all eligibility criteria before enrollment. Patients who initially failed screening could be re-screened on one occasion only at the discretion of the investigator.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tocilizumab 162 mg - Q10D or Q2W
    Arm description
    		 Participants with body weight<30 kg received 162 milligrams (mg) of tocilizumab either Q10D or Q2W for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Actemra, RoActemra
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received Sub-cutaneous Tocilizumab (SC TCZ) based on Body Weight; patients weighing < 30 kg received 162 mg of TCZ either Q10D (every ten days) or Q2W (every two weeks) for 52 weeks

    Arm title
    		 Tocilizumab 162 mg - QW
    Arm description
    		 Participants with body weight =>30 kg received 162 mg of tocilizumab QW, for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Actemra, RoActemra
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received Sub-cutaneous Tocilizumab (SC TCZ) based on Body Weight; patients weighing ≥ 30 kg received 162 mg of TCZ QW (every week) for 52 weeks

    Number of subjects in period 1
    		Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW
    Started
    25
    26
    Completed
    21
    23
    Not completed
    4
    3
         Adverse event, serious fatal
    2
    -
         Physician decision
    -
    1
         Lack of efficacy
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tocilizumab 162 mg - Q10D or Q2W
    Reporting group description
    		 Participants with body weight<30 kg received 162 milligrams (mg) of tocilizumab either Q10D or Q2W for 52 weeks.

    Reporting group title
    Tocilizumab 162 mg - QW
    Reporting group description
    		 Participants with body weight =>30 kg received 162 mg of tocilizumab QW, for 52 weeks.

    Reporting group values
    		 Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW Total
    Number of subjects
    		 25 26 51
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 5.1 ( 3.2 ) 13.3 ( 3.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 13 16 29
        Male
    		 12 10 22

    End points

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    End points reporting groups
    Reporting group title
    Tocilizumab 162 mg - Q10D or Q2W
    Reporting group description
    		 Participants with body weight<30 kg received 162 milligrams (mg) of tocilizumab either Q10D or Q2W for 52 weeks.

    Reporting group title
    Tocilizumab 162 mg - QW
    Reporting group description
    		 Participants with body weight =>30 kg received 162 mg of tocilizumab QW, for 52 weeks.

    Subject analysis set title
    Tocilizumab 162 mg - Q2W
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set includes all the patients with BW<30kg. The steady-state Cmin, Cmax and AUC parameters for those patients who received TCZ Q10D were computed as if they received the Q2W dosage regimen.

    Primary: Minimum Serum Concentration (Cmin) of Tocilizumab

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    End point title
    		 Minimum Serum Concentration (Cmin) of Tocilizumab [1] [2]
    End point description
    The Pharmacokinetic profile of Tocilizumab is evaluated in terms of Model Computed Steady-State Cmin.
    End point type
    Primary
    End point timeframe
    Samples taken at visits: - w 0,2,6,10,12,14,26,38,52 -BW<30 kg and <2years old(YO); - w 0,2,6,8,10,12,14,26,38,52-BW<30 kg and >=2YO; - w 0,1,2,4,8,13,14,26,38,52- BW>=30 kg;
    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: Descriptive statistics only were planned for this endpoint.
    [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: The missing reporting group has been replaced by the ad hoc analysis set for this endpoint.
    End point values
    		 Tocilizumab 162 mg - QW Tocilizumab 162 mg - Q2W
    Number of subjects analysed
    26
    25
    Units: mcg/mL
        median (full range (min-max))
    72.37 (19.52 to 157.8)
    64.15 (16.61 to 135.9)
    No statistical analyses for this end point

    Primary: Area Under the Concentration-Time Curve (AUC) of Tocilizumab

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    End point title
    		 Area Under the Concentration-Time Curve (AUC) of Tocilizumab [3] [4]
    End point description
    The Pharmacokinetic (PK) profile of TCZ is evaluated in terms of Model Computed Steady-State AUC.
    End point type
    Primary
    End point timeframe
    Samples taken at visits: - w 0,2,6,10,12,14,26,38,52 -BW<30 kg and <2years old(YO); - w 0,2,6,8,10,12,14,26,38,52-BW<30 kg and >=2YO; - w 0,1,2,4,8,13,14,26,38,52- BW>=30 kg;
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics only were planned for this endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The missing reporting group has been replaced by the ad hoc analysis set for this endpoint.
    End point values
    		 Tocilizumab 162 mg - QW Tocilizumab 162 mg - Q2W
    Number of subjects analysed
    26
    25
    Units: mcg*day/mL
        median (full range (min-max))
    1154 (334 to 2370)
    1298 (539 to 2792)
    No statistical analyses for this end point

    Primary: Maximum Serum Concentration (Cmax) of Tocilizumab

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    End point title
    		 Maximum Serum Concentration (Cmax) of Tocilizumab [5] [6]
    End point description
    The Pharmacokinetic profile of Tocilizumab is evaluated in terms of Model Computed Steady-State Cmax.
    End point type
    Primary
    End point timeframe
    Samples taken at visits: - w 0,2,6,10,12,14,26,38,52 -BW<30 kg and <2years old(YO); - w 0,2,6,8,10,12,14,26,38,52-BW<30 kg and >=2YO; - w 0,1,2,4,8,13,14,26,38,52- BW>=30 kg;
    Notes
    [5] - 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: Descriptive statistics only were planned for this endpoint.
    [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: The missing reporting group has been replaced by the ad hoc analysis set for this endpoint.
    End point values
    		 Tocilizumab 162 mg - QW Tocilizumab 162 mg - Q2W
    Number of subjects analysed
    26
    25
    Units: mcg/mL
        median (full range (min-max))
    89.8 (26.37 to 190.2)
    126.6 (51.67 to 265.8)
    No statistical analyses for this end point

    Secondary: Serum Interleukin-6 (IL6) Levels

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    End point title
    		 Serum Interleukin-6 (IL6) Levels
    End point description
    The Pharmacodynamic profile of TCZ is evaluated in terms of IL-6 serum concentration. 99999 indicates that the value was not estimated at that week for that reporting group.
    End point type
    Secondary
    End point timeframe
    Samples taken at visits: - w 0,2,6,10,12,14,26,38,52 -BW<30 kg and <2years old(YO); - w 0,2,6,8,10,12,14,26,38,52-BW<30 kg and >=2YO; - w 0,1,2,4,8,13,14,26,38,52- BW>=30 kg;
    End point values
    		 Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW
    Number of subjects analysed
    25 [7]
    26 [8]
    Units: pg/ml
    median (full range (min-max))
        Baseline (N=18, 21)
    28.350 (1.46 to 208.00)
    19.800 (3.12 to 153.00)
        Week 1 (N= 0, 22)
    99999 (99999 to 99999)
    36.300 (11.20 to 1160.00)
        Week 2 (N=23, 20)
    35.200 (3.12 to 935.00)
    22.200 (11.10 to 395.00)
        Week 4 (N= 6, 24)
    73.300 (11.40 to 816.00)
    27.000 (10.80 to 2530.00)
        Week 6 (N=15, 0)
    30.300 (12.10 to 618.00)
    99999 (99999 to 99999)
        Week 8 (N=16, 24)
    80.400 (3.12 to 625.00)
    33.650 (11.90 to 1130.00)
        Week 10 (N= 22, 0)
    39.600 (3.12 to 4690.00)
    99999 (99999 to 99999)
        Week 12 (N=18, 0)
    45.500 (12.00 to 482.00)
    99999 (99999 to 99999)
        Week 13 (N= 0, 13)
    99999 (99999 to 99999)
    23.600 (10.10 to 168.00)
        Week 14 (N=23, 19)
    74.600 (12.60 to 2190.00)
    28.200 (9.46 to 416.00)
        Week 26 (N=19, 22)
    50.200 (11.30 to 337.00)
    25.800 (8.40 to 906.00)
        Week 38 (N= 17, 23)
    27.200 (6.55 to 771.00)
    22.500 (7.98 to 354.00)
        Week 52 (N= 17, 20)
    40.800 (13.70 to 297.00)
    25.200 (8.43 to 182.00)
    Notes
    [7] - The number of participants analysed per every single week is reported below (N=)
    [8] - The number of participants analysed per every single week is reported below (N=)
    No statistical analyses for this end point

    Secondary: Soluble IL-6 Receptor (sIL-6R) Levels

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    End point title
    		 Soluble IL-6 Receptor (sIL-6R) Levels
    End point description
    The pharmacodynamic profile of TCZ is evaluated in terms of sIL-6R serum concentration. 99999 indicates that the value was not estimated at that week for that reporting group.
    End point type
    Secondary
    End point timeframe
    Samples taken at visits: - w 0,2,6,10,12,14,26,38,52 -BW<30 kg and <2years old(YO); - w 0,2,6,8,10,12,14,26,38,52-BW<30 kg and >=2YO; - w 0,1,2,4,8,13,14,26,38,52- BW>=30 kg;
    End point values
    		 Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW
    Number of subjects analysed
    25 [9]
    26 [10]
    Units: ng/ml
    median (full range (min-max))
        Baseline (N=19, 22)
    57.50 (21.0 to 1240.0)
    419.50 (27.1 to 1170.0)
        Week 1 (N=0, 25)
    99999 (99999 to 99999)
    447.00 (234.0 to 1020.0)
        Week 2 (N=25, 22)
    575.00 (44.3 to 1260.0)
    456.50 (149.0 to 1030.0)
        Week 4 (N=8, 25)
    705.00 (521.0 to 1060.0)
    575.00 (194.0 to 1010.0)
        Week 6 (N=15, 0)
    751.00 (43.7 to 1170.0)
    99999 (99999 to 99999)
        Week 8 (N=19, 24)
    716.00 (67.7 to 1270.0)
    738.00 (418.0 to 1090.0)
        Week 10 (N=22, 0)
    714.00 (114.0 to 1480.0)
    99999 (99999 to 99999)
        Week 12 (N=18, 0)
    716.50 (488.0 to 1190.0)
    99999 (99999 to 99999)
        Week 13 (N=0, 14)
    99999 (99999 to 99999)
    664.00 (395.0 to 1050.0)
        Week 14 (N=23, 20)
    736.00 (503.0 to 1830.0)
    710.00 (428.0 to 1070.0)
        Week 26 (N=21, 22)
    775.00 (500.0 to 1910.0)
    645.50 (346.0 to 1060.0)
        Week 38 (N=20, 23)
    782.00 (301.0 to 1420.0)
    583.00 (262.0 to 1230.0)
        Week 52 (N=18, 20)
    737.00 (270.0 to 1490.0)
    598.00 (199.0 to 1070.0)
    Notes
    [9] - The number of participants analysed per every single week is reported below (N=)
    [10] - The number of participants analysed per every single week is reported below (N=)
    No statistical analyses for this end point

    Secondary: Serum C-Reactive Protein (CRP) Levels

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    End point title
    		 Serum C-Reactive Protein (CRP) Levels
    End point description
    The pharmacodynamic profile of TCZ is evaluated in terms of CRP serum concentration. 99999 indicates that the value was not estimated at that week for that reporting group.
    End point type
    Secondary
    End point timeframe
    Samples for this analysis were taken at: W-3,0,1,2,3,4,6,8,10,12,13,14,18,22,26,30,34,38,42,46,50,52 - BW>=30kg W-3,0,2,4,6,10,14,18,22,26,30,34,38,42,46,50,52-BW<30kg - >=2YO W-3,0,2,4,6,10,12,14,18,22,26,30,34,38,42,46,50,52 -BW<30kg - <2YO
    End point values
    		 Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW
    Number of subjects analysed
    25 [11]
    26 [12]
    Units: mg/L
    median (full range (min-max))
        Baseline (N=25, 26)
    3.270 (0.20 to 186.00)
    0.305 (0.20 to 117.00)
        Week 1 (N=0, 26)
    99999 (99999 to 99999)
    0.200 (0.20 to 9.00)
        Week 2 (N=25, 23)
    0.200 (0.20 to 139.00)
    0.200 (0.20 to 1.58)
        Week 3 (N=8, 25)
    0.200 (0.20 to 0.43)
    0.200 (0.20 to 2.06)
        Week 4 (N=23, 24)
    0.200 (0.20 to 150.00)
    0.200 (0.20 to 1.27)
        Week 6 (N=16, 25)
    0.200 (0.20 to 27.70)
    0.200 (0.20 to 1.06)
        Week 8 (N=7, 24)
    0.200 (0.20 to 0.83)
    0.200 (0.20 to 1.25)
        Week 10 (N=23, 24)
    0.200 (0.20 to 22.60)
    0.200 (0.20 to 3.65)
        Week 12 (N=7, 24)
    0.200 (0.20 to 0.38)
    0.200 (0.20 to 2.55)
        Week 13 (N=0, 21)
    99999 (99999 to 99999)
    0.200 (0.20 to 2.23)
        Week 14 (N=23, 23)
    0.200 (0.20 to 0.48)
    0.200 (0.20 to 1.36)
        Week 18 (N=23, 23)
    0.200 (0.20 to 3.50)
    0.200 (0.20 to 2.61)
        Week 22 (N=23, 23)
    0.200 (0.20 to 0.36)
    0.200 (0.20 to 1.82)
        Week 26 (N=22, 23)
    0.200 (0.20 to 3.46)
    0.200 (0.20 to 1.89)
        Week 30 (N=22, 22)
    0.200 (0.20 to 0.85)
    0.200 (0.20 to 1.67)
        Week 34 (N=22, 23)
    0.200 (0.20 to 0.91)
    0.200 (0.20 to 1.95)
        Week 38 (N=21, 23)
    0.200 (0.20 to 11.90)
    0.200 (0.20 to 1.39)
        Week 42 (N=15, 23)
    0.200 (0.20 to 3.92)
    0.200 (0.20 to 1.43)
        Week 46 (N=20, 23)
    0.200 (0.20 to 0.36)
    0.200 (0.20 to 2.11)
        Week 50 (N=20, 23)
    0.200 (0.20 to 1.01)
    0.200 (0.20 to 5.00)
        Week 52 (N=17, 18)
    0.200 (0.20 to 1.23)
    0.200 (0.20 to 2.45)
    Notes
    [11] - The number of participants analysed per every single week is reported below (N=)
    [12] - The number of participants analysed per every single week is reported below (N=)
    No statistical analyses for this end point

    Secondary: Serum Erythrocyte Sedimentation Rate (ESR)

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    End point title
    		 Serum Erythrocyte Sedimentation Rate (ESR)
    End point description
    The pharmacodynamic profile of TCZ is evaluated in terms of ESR. 99999 indicates that the value was not estimated at that week for that reporting group.
    End point type
    Secondary
    End point timeframe
    Samples for this analysis were taken at: W-3,0,1,2,3,4,6,8,10,12,13,14,18,22,26,30,34,38,42,46,50,52 - BW>=30kg W-3,0,2,4,6,10,14,18,22,26,30,34,38,42,46,50,52-BW<30kg - >=2YO W-3,0,2,4,6,10,12,14,18,22,26,30,34,38,42,46,50,52 -BW<30kg - <2YO
    End point values
    		 Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW
    Number of subjects analysed
    25 [13]
    26 [14]
    Units: mm/h
    median (full range (min-max))
        Baseline (N=25, 26)
    10.00 (0.0 to 120.0)
    5.00 (0.0 to 90.0)
        Week 1 (N=0, 26)
    99999 (99999 to 99999)
    5.00 (1.0 to 50.0)
        Week 2 (N=22, 23)
    5.00 (0.0 to 40.0)
    4.00 (0.0 to 28.0)
        Week 3 (N=8, 25)
    3.50 (2.0 to 8.0)
    3.00 (1.0 to 12.0)
        Week 4 (N=23, 25)
    3.00 (0.0 to 65.0)
    4.00 (0.0 to 20.0)
        Week 6 (N=15, 25)
    3.00 (0.0 to 10.0)
    3.00 (0.0 to 9.0)
        Week 8 (N=8, 24)
    3.50 (2.0 to 9.0)
    3.00 (0.0 to 12.0)
        Week 10 (N=23, 24)
    3.00 (0.0 to 9.0)
    3.00 (0.0 to 20.0)
        Week 12 (N=7, 23)
    3.00 (2.0 to 6.0)
    3.00 (0.0 to 18.0)
        Week 13 (N=0, 21)
    99999 (99999 to 99999)
    4.00 (1.0 to 16.0)
        Week 14 (N=22, 22)
    2.00 (0.0 to 8.0)
    3.00 (1.0 to 11.0)
        Week 18 (N=22, 23)
    2.00 (0.0 to 9.0)
    4.00 (0.0 to 15.0)
        Week 22 (N=23, 23)
    3.00 (0.0 to 9.0)
    3.48 (0.0 to 20.0)
        Week 26 (N=22, 23)
    2.00 (0.0 to 9.0)
    3.00 (0.0 to 16.0)
        Week 30 (N=21, 23)
    2.00 (0.0 to 6.0)
    3.00 (0.0 to 18.0)
        Week 34 (N=22, 23)
    2.00 (0.0 to 10.0)
    3.00 (0.0 to 16.0)
        Week 38 (N=19, 23)
    2.00 (0.0 to 15.0)
    3.00 (0.0 to 25.0)
        Week 42 (N=15, 21)
    3.00 (0.0 to 12.0)
    3.00 (0.0 to 18.0)
        Week 46 (N=20, 22)
    2.00 (0.0 to 8.0)
    3.00 (0.0 to 15.0)
        Week 50 (N=21, 23)
    2.00 (0.0 to 10.0)
    2.00 (0.0 to 17.0)
        Week 52 (N=19, 23)
    2.00 (0.0 to 5.0)
    2.00 (1.0 to 24.0)
    Notes
    [13] - The number of participants analysed per every single week is reported below (N=)
    [14] - The number of participants analysed per every single week is reported below (N=)
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-TCZ Antibodies

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    End point title
    		 Number of Participants with Anti-TCZ Antibodies
    End point description
    The pharmacodynamic profile of TCZ is evaluated in terms of number of Participants with treatment-induced Anti-Tocilizumab Antibodies.
    End point type
    Secondary
    End point timeframe
    Anti-TCZ antibodies were measured at approximately 3 month intervals during the study and at the last study visit or at the time of early withdrawal from the study.
    End point values
    		 Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW
    Number of subjects analysed
    25
    26
    Units: Number of participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with At Least 1 Adverse Event (AE)

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    End point title
    		 Number of Participants with At Least 1 Adverse Event (AE)
    End point description
    The safety profile of TCZ is evaluated in terms of number of participants with at least one AE and one SAE.
    End point type
    Secondary
    End point timeframe
    All AEs, are reported after initiation of study drug until 3 months after the last dose of study drug. After this period, any deaths, SAEs, or other AEs of concern that are believed to be related to prior treatment with study drug are reported.
    End point values
    		 Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW
    Number of subjects analysed
    25
    26
    Units: Number of participants
        Any AE
    25
    25
        SAE
    5
    2
    No statistical analyses for this end point

    Secondary: Number of participants reporting adverse events of special interest (AESI)

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    End point title
    		 Number of participants reporting adverse events of special interest (AESI)
    End point description
    The safety profile of TCZ is evaluated in terms of number of participants reporting AESI. Multiple occurrences of the same AE in one individual are counted once at the highest grade for this preferred term. Severity refers to the intensity of an AE according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) i.e. from grade 1 (mild) up to grade 5 (Death related to adverse event).
    End point type
    Secondary
    End point timeframe
    All AEs, are reported after initiation of study drug until 3 months after the last dose of study drug. After this period, any deaths, SAEs, or other AEs of concern that are believed to be related to prior treatment with study drug are reported.
    End point values
    		 Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW
    Number of subjects analysed
    25
    26
    Units: Number of participants
        Sepsis - grade 5
    1
    0
        Oral Candidiasis - grade 2
    1
    0
        Pneumonia - grade 3
    1
    0
        Pneumonia - grade 4
    1
    0
        Abscess soft tissue - grade 3
    1
    0
        Injection Site Reactions - grade 1
    5
    12
        Injection Site Reactions - grade 2
    0
    3
        Injection Site Reactions - grade 3
    1
    1
        Hypersensitivity - grade 1
    1
    0
        Platelet Count Decreased - grade 2
    1
    0
        Pyrexia - grade 1
    0
    1
        Pruritus - grade 1
    1
    0
        Pulmonary Haemorrage - grade 5
    1
    0
    No statistical analyses for this end point

    Secondary: Number of patients reporting clinical laboratory abnormalities

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    End point title
    		 Number of patients reporting clinical laboratory abnormalities
    End point description
    The safety profile of TCZ is evaluated in terms of number of patients with clinical laboratory abnormalities. Severity refers to the intensity of an AE according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) i.e. from grade 1 (mild) up to grade 5 (Death related to adverse event). For a patient with multiple post-baseline lab abnormalities, the highest (worst) grade of these abnormalities for the given lab test is reported.
    End point type
    Secondary
    End point timeframe
    All AEs, are reported after initiation of study drug until 3 months after the last dose of study drug. After this period, any deaths, SAEs, or other AEs of concern that are believed to be related to prior treatment with study drug are reported.
    End point values
    		 Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW
    Number of subjects analysed
    25
    26
    Units: Number of participants
        Hemoglobin Low - grade 1
    3
    2
        Hemoglobin Low - grade 2
    1
    0
        Hemoglobin Low - grade 3
    1
    0
        Hemoglobin High - grade 1
    5
    0
        Lymphocytes Abs Low - grade 1
    6
    10
        Lymphocytes Abs Low - grade 2
    1
    0
        Lymphocytes Abs Low - grade 3
    0
    1
        Lymphocytes Abs High - grade 2
    4
    3
        Neutrophils, Total, Abs Low - grade 1
    0
    3
        Neutrophils, Total, Abs Low - grade 2
    8
    5
        Neutrophils, Total, Abs Low - grade 3
    4
    8
        Platelet Low - grade 1
    10
    2
        White Blood Cell Count Low - grade 1
    12
    10
        White Blood Cell Count Low - grade 2
    2
    5
        White Blood Cell Count Low - grade 3
    1
    0
        Alkaline Phosphatase High - grade 1
    3
    3
        Alkaline Phosphatase High - grade 2
    1
    0
        Bilirubin High - grade 1
    1
    3
        Bilirubin High - grade 2
    0
    2
        Blood Glucose (fasting) Low - grade 1
    12
    2
        Blood Glucose (fasting) Low - grade 2
    2
    0
        Blood Glucose (fasting) High - grade 1
    5
    7
        Calcium Low - grade 1
    1
    0
        Calcium Low - grade 2
    0
    1
        Calcium Low - grade 4
    0
    1
        Calcium High - grade 1
    9
    5
        Creatinine High - grade 1
    12
    24
        Creatinine High - grade 2
    9
    1
        Glucose Low - grade 1
    3
    2
        Phosphorus Low - grade 1
    0
    1
        Potassium Low - grade 2
    1
    1
        Potassium High - grade 1
    1
    0
        Potassium High - grade 2
    0
    1
        Potassium High - grade 3
    0
    1
        Potassium High - grade 4
    0
    1
        SGOT/AST High - grade 1
    3
    7
        SGOT/AST High - grade 2
    1
    0
        SGOT/AST High - grade 3
    1
    0
        SGPT/ALT High - grade 1
    6
    6
        SGPT/ALT High - grade 2
    1
    2
        SGPT/ALT High - grade 3
    1
    0
        SGPT/ALT High - grade 4
    1
    0
        Uric Acid High - grade 3
    8
    5
        Cholesterol High - grade 1
    2
    1
        Triglycerides High - grade 1
    3
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs, are reported after initiation of study drug until 3 months after the last dose of study drug. After this period, any deaths, SAEs, or other AEs of concern that are believed to be related to prior treatment with study drug are reported.
    Adverse event reporting additional description
    The safety analyses will include all enrolled patients who received at least one dose of study drug, with patients grouped according to the treatment received (safety population). The safety analysis population will include all patients who received at least one dose of study drug and who have at least one post-dose assessment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Tocilizumab 162 mg - Q10D or Q2W
    Reporting group description
    		 Participants with body weight<30 kg received 162 milligrams (mg) of tocilizumab either Q10D or Q2W for 52 weeks.

    Reporting group title
    Tocilizumab 162 mg - QW
    Reporting group description
    		 Participants with body weight =>30 kg received 162 mg of tocilizumab QW, for 52 weeks.

    Serious adverse events
    		 Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 25 (20.00%)
    2 / 26 (7.69%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PULMONARY HAEMORRHAGE
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    JUVENILE IDIOPATHIC ARTHRITIS
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ABSCESS SOFT TISSUE
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORAL CANDIDIASIS
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tocilizumab 162 mg - Q10D or Q2W Tocilizumab 162 mg - QW
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 25 (92.00%)
    24 / 26 (92.31%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Injury, poisoning and procedural complications
    ARTHROPOD BITE
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 26 (7.69%)
         occurrences all number
    3
    3
    CONTUSION
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 26 (7.69%)
         occurrences all number
    3
    2
    FALL
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    LIGAMENT SPRAIN
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    3
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    0 / 25 (0.00%)
    6 / 26 (23.08%)
         occurrences all number
    0
    15
    Blood and lymphatic system disorders
    LEUKOPENIA
         subjects affected / exposed
    1 / 25 (4.00%)
    5 / 26 (19.23%)
         occurrences all number
    1
    8
    NEUTROPENIA
         subjects affected / exposed
    5 / 25 (20.00%)
    8 / 26 (30.77%)
         occurrences all number
    21
    11
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 26 (11.54%)
         occurrences all number
    2
    4
    INJECTION SITE SWELLING
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    9
    INJECTION SITE REACTION
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    10
    INJECTION SITE PRURITUS
         subjects affected / exposed
    0 / 25 (0.00%)
    6 / 26 (23.08%)
         occurrences all number
    0
    12
    INJECTION SITE PAPULE
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    41
    INJECTION SITE PAIN
         subjects affected / exposed
    1 / 25 (4.00%)
    5 / 26 (19.23%)
         occurrences all number
    1
    11
    INJECTION SITE INDURATION
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    INJECTION SITE OEDEMA
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    3
    INJECTION SITE ERYTHEMA
         subjects affected / exposed
    1 / 25 (4.00%)
    9 / 26 (34.62%)
         occurrences all number
    6
    18
    Ear and labyrinth disorders
    EAR PAIN
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 26 (15.38%)
         occurrences all number
    2
    6
    CONSTIPATION
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    DIARRHOEA
         subjects affected / exposed
    4 / 25 (16.00%)
    3 / 26 (11.54%)
         occurrences all number
    5
    5
    NAUSEA
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    ODYNOPHAGIA
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    5
    VOMITING
         subjects affected / exposed
    3 / 25 (12.00%)
    6 / 26 (23.08%)
         occurrences all number
    4
    6
    Hepatobiliary disorders
    HYPERTRANSAMINASAEMIA
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    6 / 25 (24.00%)
    6 / 26 (23.08%)
         occurrences all number
    13
    9
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 26 (15.38%)
         occurrences all number
    2
    5
    RHINORRHOEA
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    4
    2
    BRONCHOSPASM
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Skin and subcutaneous tissue disorders
    PRURITUS
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    RASH
         subjects affected / exposed
    4 / 25 (16.00%)
    4 / 26 (15.38%)
         occurrences all number
    4
    5
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    3
    ARTHRITIS
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    BACK PAIN
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    JUVENILE IDIOPATHIC ARTHRITIS
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    NECK PAIN
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    3
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    EAR INFECTION
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    5
    GASTROENTERITIS
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 26 (7.69%)
         occurrences all number
    3
    2
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    HAND-FOOT-AND-MOUTH DISEASE
         subjects affected / exposed
    4 / 25 (16.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    PARONYCHIA
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    PHARYNGITIS
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    3
    RHINITIS
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 26 (15.38%)
         occurrences all number
    2
    4
    SINUSITIS
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    3
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    6 / 25 (24.00%)
    5 / 26 (19.23%)
         occurrences all number
    16
    7
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    8 / 25 (32.00%)
    5 / 26 (19.23%)
         occurrences all number
    16
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2013
    Protocol Version 2 removed the Juvenile Arthritis Multidimensional Assessment Report (JAMAR) as a PRO tool for legal reasons, and replaced it with the CHAQ functional ability instrument. As the CHAQ uses 100 mm VAS scales as opposed to the 21-circle scale used in JAMAR, all other assessments using the 21-circle scale were switched to the 100 mm VAS scale for the purposes of consistency. Additionally, the immunogenicity testing requirements were updated for patients who withdrew due to hypersensitivity or anaphylaxis, and the dose interval changes for patients whose BW increased or decreased above or below the 30 kg threshold were clarified.
    08 May 2013
    Protocol Version 3 was a country specific amendment for Russia, which revised the inclusion criteria for the age range of patients to 12−17 years of age.
    05 Aug 2013
    The key changes in Protocol Version 4 were to limit the number of patients switching from TCZ IV to TCZ SC to no more than 50% of the total number of subjects and to include the request to collect information on the prior four IV infusions for patients switching from TCZ IV to TCZ SC.
    02 Mar 2015
    Protocol Version 5 changed the dosing regimen for patients weighing < 30 kg from Q10D to Q2W following the review of the planned interim analysis. This change was applicable to all newly enrolled patients weighing < 30 kg as well as to patients weighing  30 kg already enrolled in the study and receiving Q10D as per the initial dosing regimen. It should be noted that this Protocol Amendment was finalized but not submitted to the Health Authorities or study sites as further updates were identified prior to submission.
    23 Jun 2015
    Protocol Version 6 included the change in dosing regimen for patients weighing < 30 kg (i.e., Q10D to Q2W) as described in Version 5 and was submitted to the Health Authorities and study sites. It was planned that patients weighing < 30 kg enrolled prior to the interim analysis would switch from a Q10D to a Q2W dosing regimen; however, these patients had completed the study by the time this protocol amendment was approved and implemented. Additional minor changes were included in this Protocol Amendment.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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