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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Double-Blind Placebo-Controlled Study to Assess the Efficacy and Safety of Tocilizumab in Subjects With Giant Cell Arteritis

    Summary
    EudraCT number
    2011-006022-25
    Trial protocol
    IT   SE   AT   DE   DK   GB   PT   NL   ES   BE   PL  
    Global end of trial date
    04 Jun 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    19 Jun 2019
    First version publication date
    26 Apr 2017
    Other versions
    v1
    Version creation reason

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    WA28119
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01791153
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective for this study was to evaluate the efficacy of tocilizumab compared to placebo, in combination with a 26-week prednisone taper regimen, in participants with giant cell arteritis (GCA), as measured by the proportion of participants in sustained remission at Week 52 following induction and adherence to the protocol-defined prednisone taper regimen.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice. Approval from the Independent Ethics Committee/Institutional Review Board was obtained before study start and was documented in a letter to the Investigator specifying the date on which the committee met and granted the approval.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    United States: 50
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 78
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Norway: 4
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Portugal: 3
    Worldwide total number of subjects
    250
    EEA total number of subjects
    198
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    82
    From 65 to 84 years
    166
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    The study consists of 2 parts: a 52-week double-blind treatment period (Part 1) followed by a 104-week open label long-term follow-up period (Part 2).

    Pre-assignment
    Screening details
    Of the 363 participants screened, a total of 251 participants were randomized into the study. One participant who was randomized to the "Tocilizumab q2w + 26 weeks prednisone taper" group withdrew on the same day of randomization and did not receive any study treatment. This participant was not included in any of the study analyses.

    Period 1
    Period 1 title
    Part 1: Blinded Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part 1: Tocilizumab qw + 26 weeks prednisone taper
    Arm description
    Participants received tocilizumab at a dose of 162 milligrams (mg) as subcutaneous (SC) injection every week (qw) up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra, RO4877533
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab was administered at a dose of 162 mg as SC injection qw for 52 weeks in Part 1 of the study.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone was administered at tapering oral doses daily for 26 weeks according to the protocol-defined schedule in Part 1 of the study.

    Investigational medicinal product name
    Prednisone placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone placebo was administered daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.

    Arm title
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper
    Arm description
    Participants received tocilizumab at a dose of 162 mg as SC injection every 2 weeks (q2w) (and tocilizumab placebo q2w starting from Week 2) up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra, RO4877533
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab was administered at a dose of 162 mg as SC injection q2w for 52 weeks in Part 1 of the study.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone was administered at tapering oral doses daily for 26 weeks according to the protocol-defined schedule in Part 1 of the study.

    Investigational medicinal product name
    Prednisone placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone placebo was administered daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.

    Investigational medicinal product name
    Tocilizumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab placebo was administered as SC injection q2w (starting from Week 2) for 52 weeks in Part 1 of the study.

    Arm title
    Part 1: Placebo + 26 weeks prednisone taper
    Arm description
    Participants received tocilizumab placebo as SC injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.
    Arm type
    Placebo

    Investigational medicinal product name
    Tocilizumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab placebo was administered as SC injection qw for 52 weeks in Part 1 of the study.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone was administered at tapering oral doses daily for 26 weeks according to the protocol-defined schedule in Part 1 of the study.

    Investigational medicinal product name
    Prednisone placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone placebo was administered daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.

    Arm title
    Part 1: Placebo + 52 weeks prednisone taper
    Arm description
    Participants received tocilizumab placebo as SC injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses for 52 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Tocilizumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab placebo was administered as SC injection qw for 52 weeks in Part 1 of the study.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone was administered at tapering oral doses daily for 52 weeks according to the protocol-defined schedule in Part 1 of the study.

    Investigational medicinal product name
    Prednisone placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone placebo was administered daily according to the protocol-defined schedule in Part 1 of the study.

    Number of subjects in period 1
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper
    Started
    100
    49
    50
    51
    Completed
    85
    41
    44
    46
    Not completed
    15
    8
    6
    5
         Protocol deviation
    -
    -
    -
    1
         Physician decision
    -
    -
    -
    1
         Lack of efficacy
    1
    3
    2
    2
         Non-Compliance
    1
    -
    -
    -
         Adverse event, non-fatal
    7
    3
    2
    -
         Consent withdrawn by subject
    6
    2
    2
    1
    Period 2
    Period 2 title
    Part 2: Open-label Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part 2: No Tocilizumab (Placebo in Part 1)
    Arm description
    Participants did not receive tocilizumab in Part 2 from Week 52 up to Week 156. These participants received placebo during Part 1 (Weeks 1 to 52).
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Part 2: No Tocilizumab (Tocilizumab in Part 1)
    Arm description
    Pa rticipants did not receive tocilizumab in Part 2 from Week 52 up to Week 156. These participants received tocilizumab during Part 1 (Weeks 1 to 52).
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Part 2: Tocilizumab (Placebo in Part 1)
    Arm description
    Participants received open-label tocilizumab as determined by the investigator during Part 2 of the study (from Week 52 up to Week 156). These participants received placebo during Part 1 (Weeks 1 to 52).
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra, RO4877533
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab was administered as SC injection qw for 104 weeks in Part 2 from Week 52 up to Week 156.

    Arm title
    Part 2: Tocilizumab (Tocilizumab in Part 1)
    Arm description
    Participants received open-label tocilizumab as determined by the investigator during Part 2 of the study (from Week 52 up to Week 156). These participants received tocilizumab during Part 1 (Weeks 1 to 52).
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra, Actemra, RO4877533
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tocilizumab was administered as SC injection qw for 104 weeks in Part 2 from Week 52 up to Week 156.

    Number of subjects in period 2 [1]
    Part 2: No Tocilizumab (Placebo in Part 1) Part 2: No Tocilizumab (Tocilizumab in Part 1) Part 2: Tocilizumab (Placebo in Part 1) Part 2: Tocilizumab (Tocilizumab in Part 1)
    Started
    40
    58
    50
    67
    Completed
    38
    54
    44
    61
    Not completed
    2
    4
    6
    6
         Death
    -
    1
    1
    1
         Physician decision
    1
    1
    -
    -
         Lack of efficacy
    -
    -
    -
    1
         Adverse event, non-fatal
    -
    1
    1
    2
         Consent withdrawn by subject
    1
    1
    3
    2
         Lost to follow-up
    -
    -
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants, who completed the Part 1 blinded period, started the Part 2 open-label period. The arms in Part 2 are based on type of treatment received during Part 2 as well as treatment received during Part 1.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Tocilizumab qw + 26 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab at a dose of 162 milligrams (mg) as subcutaneous (SC) injection every week (qw) up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.

    Reporting group title
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab at a dose of 162 mg as SC injection every 2 weeks (q2w) (and tocilizumab placebo q2w starting from Week 2) up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.

    Reporting group title
    Part 1: Placebo + 26 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab placebo as SC injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.

    Reporting group title
    Part 1: Placebo + 52 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab placebo as SC injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses for 52 weeks.

    Reporting group values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper Total
    Number of subjects
    100 49 50 51 250
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    32 17 16 17 82
        Elderly (From 65-84 years)
    67 31 34 34 166
        Elderly 85 years and over
    1 1 0 0 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    69.5 ± 8.5 69.4 ± 8.29 69.3 ± 8.14 67.8 ± 7.7 -
    Gender Categorical
    Units: Subjects
        Female
    78 34 38 37 187
        Male
    22 15 12 14 63

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Tocilizumab qw + 26 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab at a dose of 162 milligrams (mg) as subcutaneous (SC) injection every week (qw) up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.

    Reporting group title
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab at a dose of 162 mg as SC injection every 2 weeks (q2w) (and tocilizumab placebo q2w starting from Week 2) up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.

    Reporting group title
    Part 1: Placebo + 26 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab placebo as SC injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.

    Reporting group title
    Part 1: Placebo + 52 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab placebo as SC injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses for 52 weeks.
    Reporting group title
    Part 2: No Tocilizumab (Placebo in Part 1)
    Reporting group description
    Participants did not receive tocilizumab in Part 2 from Week 52 up to Week 156. These participants received placebo during Part 1 (Weeks 1 to 52).

    Reporting group title
    Part 2: No Tocilizumab (Tocilizumab in Part 1)
    Reporting group description
    Pa rticipants did not receive tocilizumab in Part 2 from Week 52 up to Week 156. These participants received tocilizumab during Part 1 (Weeks 1 to 52).

    Reporting group title
    Part 2: Tocilizumab (Placebo in Part 1)
    Reporting group description
    Participants received open-label tocilizumab as determined by the investigator during Part 2 of the study (from Week 52 up to Week 156). These participants received placebo during Part 1 (Weeks 1 to 52).

    Reporting group title
    Part 2: Tocilizumab (Tocilizumab in Part 1)
    Reporting group description
    Participants received open-label tocilizumab as determined by the investigator during Part 2 of the study (from Week 52 up to Week 156). These participants received tocilizumab during Part 1 (Weeks 1 to 52).

    Primary: Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 26 weeks prednisone taper)

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    End point title
    Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 26 weeks prednisone taper) [1]
    End point description
    Remission was defined as the absence of flare and normalization of the C-reactive protein (CRP) (less than [<] 1 milligram per deciliter [mg/dL]). Sustained remission was defined as the absence of flare following induction of remission within 12 weeks of randomization and maintained up to Week 52. Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or erythrocyte sedimentation rate (ESR) greater than or equal to (>/=) 30 millimeters per hour (mm/hr) attributable to GCA. A single CRP elevation (>/=1 mg/dL) was not considered as a sign of flare, unless the CRP remained elevated (>/=1 mg/dL) at the next study visit. Intent-to-treat (ITT) population included all participants randomized into the study who received at least one administration of study drug.
    End point type
    Primary
    End point timeframe
    Week 52
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary endpoint evaluated the proportions of patients in sustained remission in the TCZ groups compared to the 26-week placebo group. Therefore, the 52-week placebo group is not included in this analysis.
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects analysed
    100
    49
    50
    Units: percentage of participants
        number (not applicable)
    56.0
    53.1
    14.0
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (less than or equal to [</=] 30 mg/day, greater than [>] 30 mg/day).
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in response rates
    Point estimate
    42
    Confidence interval
         level
    99.5%
         sides
    2-sided
         lower limit
    18
         upper limit
    66
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in response rates
    Point estimate
    39.06
    Confidence interval
         level
    99.5%
         sides
    2-sided
         lower limit
    12.46
         upper limit
    65.66

    Secondary: Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 52 weeks prednisone taper)

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    End point title
    Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 52 weeks prednisone taper) [2]
    End point description
    Remission was defined as the absence of flare and normalization of the CRP (<1 mg/dL). Sustained remission was defined as the absence of flare following induction of remission within 12 weeks of randomization and maintained up to Week 52. Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or ESR >/=30 mm/hr attributable to GCA. A single CRP elevation (>/=1 mg/dL) was not considered as a sign of flare, unless the CRP remained elevated (>/=1 mg/dL) at the next study visit. ITT population.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [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 key secondary endpoint evaluated the proportions of patients in sustained remission in the TCZ groups compared to the 52-week placebo group. Therefore, the 26-week placebo group is not included in this analysis.
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects analysed
    100
    49
    51
    Units: percentage of participants
        number (not applicable)
    56.0
    53.1
    17.6
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    Method
    Parameter type
    Difference in response rates
    Point estimate
    38.35
    Confidence interval
         level
    99.5%
         sides
    2-sided
         lower limit
    17.89
         upper limit
    58.81
    Notes
    [3] - The tocilizumab group was to be considered as non-inferior to the placebo group if the lower limit of the two-sided 99.5% confidence interval was >/= -22.5%.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    Method
    Parameter type
    Difference in response rates
    Point estimate
    35.41
    Confidence interval
         level
    99.5%
         sides
    2-sided
         lower limit
    10.41
         upper limit
    60.41
    Notes
    [4] - The tocilizumab group was to be considered as non-inferior to the placebo group if the lower limit of the two-sided 99.5% confidence interval was >/= -22.5%.

    Secondary: Time to First GCA Disease Flare

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    End point title
    Time to First GCA Disease Flare
    End point description
    Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or ESR >/=30 mm/hr attributable to GCA. Participants who withdrew from the study prior to Week 52 were censored from the time of withdrawal. ITT population. Value "99999" in results indicates that data could not be calculated due to low number of participants who had an event.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects analysed
    100
    49
    50
    51
    Units: days
        median (confidence interval 99%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    165.0 (120.0 to 260.0)
    295.0 (168.0 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The treatment groups were compared using a Cox proportional hazards model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.23
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.11
         upper limit
    0.46
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The treatment groups were compared using a Cox proportional hazards model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0011
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.39
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    0.82
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The treatment groups were compared using a Cox proportional hazards model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0001
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.28
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.12
         upper limit
    0.66
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    The treatment groups were compared using a Cox proportional hazards model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0316
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.48
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    1.16

    Secondary: Total Cumulative Prednisone Dose

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    End point title
    Total Cumulative Prednisone Dose
    End point description
    The median total cumulative prednisone dose over the 52 weeks for each treatment group and the corresponding 95% confidence intervals are presented. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects analysed
    100
    49
    50
    51
    Units: mg
        median (confidence interval 95%)
    1862.00 (1582.0 to 1942.0)
    1862.00 (1568.0 to 2239.5)
    3296.00 (2729.5 to 4023.5)
    3817.50 (2817.5 to 4425.5)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The treatment groups were compared using a Van Elteren's test stratified by starting prednisone dose (<=30 mg/day, > 30 mg/day).
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Van Elteren's test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The treatment groups were compared using a Van Elteren's test stratified by starting prednisone dose (<=30 mg/day, > 30 mg/day).
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Van Elteren's test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The treatment groups were compared using a Van Elteren's test stratified by starting prednisone dose (<=30 mg/day, > 30 mg/day).
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0003
    Method
    Van Elteren's test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    The treatment groups were compared using a Van Elteren's test stratified by starting prednisone dose (<=30 mg/day, > 30 mg/day).
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Van Elteren's test
    Confidence interval

    Secondary: Change From Baseline in Short Form (SF)-36 Questionnaire Score at Week 52

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    End point title
    Change From Baseline in Short Form (SF)-36 Questionnaire Score at Week 52
    End point description
    The SF-36 is a standardized questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical Component Score (PCS) and Mental Component Score (MCS). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). A positive change from baseline indicates improvement. No imputation was used for missing data. Data was set to missing for participants who received escape therapy. ITT population. Here, 'Number of Subject Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects analysed
    97
    49
    48
    49
    Units: units on a scale
    arithmetic mean (standard deviation)
        PCS: Baseline (n=97,49,48,49)
    43.10 ± 9.43
    40.62 ± 8.00
    42.65 ± 10.87
    41.12 ± 9.97
        PCS: Change at Week 52 (n=59,26,9,18)
    5.37 ± 7.38
    2.71 ± 8.86
    2.08 ± 12.11
    -2.80 ± 6.98
        MCS: Baseline (n=97,49,48,49)
    42.77 ± 12.43
    47.67 ± 12.59
    42.73 ± 12.13
    40.45 ± 13.73
        MCS: Change at Week 52 (n=59,26,9,18)
    8.21 ± 10.35
    1.98 ± 7.17
    4.99 ± 7.54
    2.60 ± 10.56
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    MCS: Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8067
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    0.61
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -5.86
         upper limit
    7.07
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    MCS: Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0252
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    4.44
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -0.69
         upper limit
    9.56
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    MCS: Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8374
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    -0.56
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -7.64
         upper limit
    6.53
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    MCS: Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1468
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    3.27
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -2.59
         upper limit
    9.14
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    PCS: Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.057
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    4.38
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -1.58
         upper limit
    10.34
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    PCS: Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0024
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    5.59
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    10.32
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    PCS: Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2218
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    3.04
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -3.43
         upper limit
    9.51
    Statistical analysis title
    Statistical Analysis 8
    Statistical analysis description
    PCS: Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0412
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    4.25
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -1.14
         upper limit
    9.64

    Secondary: Change From Baseline in Patient Global Assessment (PGA) of Disease Activity Assessed Using Visual Analogue Scale (VAS) at Week 52

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    End point title
    Change From Baseline in Patient Global Assessment (PGA) of Disease Activity Assessed Using Visual Analogue Scale (VAS) at Week 52
    End point description
    Participants assessed their current disease activity on a 0-100 millimeter (mm) VAS, where 0 mm = no disease activity and 100 mm = maximum disease activity. A negative change from baseline indicates improvement. ITT population. Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects analysed
    100
    49
    49
    51
    Units: mm
    arithmetic mean (standard deviation)
        Baseline (n=100,49,49,51)
    43.61 ± 25.66
    46.65 ± 25.60
    35.73 ± 28.15
    47.78 ± 27.80
        Change at Week 52 (n=60,26,11,18)
    -19.68 ± 33.64
    -22.69 ± 22.41
    -8.45 ± 24.81
    -10.00 ± 35.12
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0312
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    -15.6
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -34.3
         upper limit
    3.1
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0476
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    -11.8
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -27.2
         upper limit
    3.6
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0059
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    -21.9
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -42.4
         upper limit
    -1.4
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.
    Comparison groups
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0081
    Method
    Repeated measures model
    Parameter type
    Differences in Least Square Means
    Point estimate
    -18.2
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -35.8
         upper limit
    -0.5

    Secondary: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State of Tocilizumab

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    End point title
    Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State of Tocilizumab [5]
    End point description
    AUCtau is the model-predicted area under the tocilizumab serum concentration versus time curve from time zero to the end of dosing interval. AUCtau is measured in microgram*day per milliliter (mcg*day/mL). Pharmacokinetics (PK)-evaluable population included all participants who received at least one tocilizumab injection and had at least one PK sample with detectable results taken at any time during the study.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0])
    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 evaluated the concentrations of TCZ in serum samples and is therefore not applicable for the two treatment arms, which received placebo.
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper
    Number of subjects analysed
    100
    49
    Units: mcg*day/mL
        arithmetic mean (standard deviation)
    499.2 ± 210.4
    227.2 ± 165.4
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration at Steady State (Cmax,ss) of Tocilizumab

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    End point title
    Maximum Serum Concentration at Steady State (Cmax,ss) of Tocilizumab [6]
    End point description
    Cmax,ss is maximum model-predicted serum steady state concentration of tocilizumab measured in micrograms per milliliter (mcg/mL). PK-evaluable population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0])
    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 evaluated the concentrations of TCZ in serum samples and is therefore not applicable for the two treatment arms, which received placebo.
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper
    Number of subjects analysed
    100
    49
    Units: mcg/mL
        arithmetic mean (standard deviation)
    73 ± 30.4
    19.3 ± 12.8
    No statistical analyses for this end point

    Secondary: Minimum Serum Concentration at Steady State (Cmin,ss) of Tocilizumab

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    End point title
    Minimum Serum Concentration at Steady State (Cmin,ss) of Tocilizumab [7]
    End point description
    Cmin,ss is minimum model-predicted serum steady state concentration of tocilizumab measured in mcg/mL. PK-evaluable population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0])
    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 evaluated the concentrations of TCZ in serum samples and is therefore not applicable for the two treatment arms, which received placebo.
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper
    Number of subjects analysed
    100
    49
    Units: mcg/mL
        arithmetic mean (standard deviation)
    68.1 ± 29.5
    11.1 ± 10.3
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Ctrough) of Tocilizumab

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    End point title
    Minimum Observed Serum Concentration (Ctrough) of Tocilizumab [8]
    End point description
    Ctrough is minimum observed serum concentration of tocilizumab measured in mcg/mL. PK-evaluable population. Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    Predose (Hour 0) at Baseline and Week 52
    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 evaluated the concentrations of TCZ in serum samples and is therefore not applicable for the two treatment arms, which received placebo.
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper
    Number of subjects analysed
    99
    48
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Baseline (n= 99, 48)
    0.07 ± 0.72
    0.00 ± 0.02
        Week 52 (n= 72, 33)
    67.93 ± 34.40
    12.22 ± 10.02
    No statistical analyses for this end point

    Secondary: Serum Interleukin-6 (IL-6) Level

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    End point title
    Serum Interleukin-6 (IL-6) Level
    End point description
    Safety population. Here, 'n' signifies the number of participants evaluable at specified time point for different arms, respectively
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects analysed
    100
    49
    50
    51
    Units: picograms per milliliter (pg/mL)
    arithmetic mean (standard deviation)
        Baseline (n=91,44,50,47)
    8.79 ± 10.01
    16.29 ± 31.23
    12.73 ± 18.04
    8.31 ± 9.47
        Week 52 (n=69,32,28,30)
    65.99 ± 84.92
    52.70 ± 33.10
    35.96 ± 149.65
    10.85 ± 15.17
    No statistical analyses for this end point

    Secondary: Serum Soluble IL-6 Receptor (sIL-6R) Level

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    End point title
    Serum Soluble IL-6 Receptor (sIL-6R) Level
    End point description
    Safety population. Here, 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects analysed
    100
    49
    50
    51
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n=99,48,50,50)
    51.34 ± 61.98
    50.82 ± 63.51
    42.07 ± 11.32
    40.37 ± 10.84
        Week 52 (n=73,33,33,31)
    600.53 ± 217.52
    464.30 ± 153.64
    76.44 ± 149.20
    64.80 ± 105.13
    No statistical analyses for this end point

    Secondary: Erythrocyte Sedimentation Rate (ESR)

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    End point title
    Erythrocyte Sedimentation Rate (ESR)
    End point description
    ESR is a laboratory test that provides a non­specific measure of inflammation. The test assesses the rate at which red blood cells fall in a test tube. Normal range is 0-30 mm/hr. A higher rate is consistent with inflammation. Safety population. Here, 'n' signifies the number of participants evaluable at specified time point for different arms, respectively
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects analysed
    100
    49
    50
    51
    Units: mm/hr
    median (inter-quartile range (Q1-Q3))
        Baseline (n=99,49,50,51)
    19.00 (10.00 to 35.00)
    15.00 (10.00 to 30.00)
    23.00 (9.00 to 36.00)
    20.00 (8.00 to 38.00)
        Week 52 (n=76,35,35,33)
    3.00 (2.00 to 5.00)
    5.00 (2.00 to 7.00)
    20.00 (11.00 to 36.00)
    24.00 (10.00 to 37.00)
    No statistical analyses for this end point

    Secondary: C-Reactive Protein (CRP) Level

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    End point title
    C-Reactive Protein (CRP) Level
    End point description
    The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. Safety population. Here, 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects analysed
    100
    49
    50
    51
    Units: milligrams per liter (mg/L)
    median (inter-quartile range (Q1-Q3))
        Baseline (n=100,49,50,51)
    3.67 (1.02 to 9.26)
    4.52 (1.55 to 9.75)
    3.64 (1.20 to 9.59)
    3.56 (1.17 to 7.24)
        Week 52 (n=76,35,35,33)
    0.30 (0.20 to 0.59)
    0.33 (0.20 to 0.72)
    4.90 (2.25 to 9.25)
    8.12 (2.02 to 14.40)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Tocilizumab Antibodies

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    End point title
    Percentage of Participants With Anti-Tocilizumab Antibodies
    End point description
    All samples were tested by screening assay, and those samples that were positive were further analyzed by a confirmation assay to confirm specificity. Percentage of participants who has a positive confirmation assay result any time after the initial drug administration with a negative confirmation assay result at baseline was reported. Safety population included all participants who received at least one administration of study drug and provided at least one post-dose safety assessment. Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper
    Number of subjects analysed
    95
    46
    49
    47
    Units: percentage of participants
        number (not applicable)
    1.1
    6.5
    2.0
    2.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 156 weeks
    Adverse event reporting additional description
    Safety population
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Part 1: Tocilizumab qw + 26 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab at a dose of 162 mg as SC injection qw for 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks.

    Reporting group title
    Part 1: Tocilizumab q2w + 26 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab at a dose of 162 mg as SC injection q2w for 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks.

    Reporting group title
    Part 1: Placebo + 26 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab placebo as SC injection for 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks.

    Reporting group title
    Part 1: Placebo + 52 weeks prednisone taper
    Reporting group description
    Participants received tocilizumab placebo as SC injection for 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses for 52 weeks.

    Reporting group title
    Part 2: No Tocilizumab (Placebo in Part 1)
    Reporting group description
    Participants did not receive tocilizumab in Part 2 from Week 52 up to Week 156.These participants received placebo during Part 1 (Weeks 1 to 52).

    Reporting group title
    Part 2: No Tocilizumab (Tocilizumab in Part 1)
    Reporting group description
    Participants did not receive tocilizumab in Part 2 from Week 52 up to Week 156. These participants received tocilizumab during Part 1 (Weeks 1 to 52).

    Reporting group title
    Part 2: Tocilizumab (Placebo in Part 1)
    Reporting group description
    Participants received open-label tocilizumab as determined by the investigator during Part 2 of the study (from Week 52 up to Week 156). These participants received placebo during Part 1 (Weeks 1 to 52).

    Reporting group title
    Part 2: Tocilizumab (Tocilizumab in Part 1)
    Reporting group description
    Participants received open-label tocilizumab as determined by the investigator during Part 2 of the study (from Week 52 up to Week 156). These participants received tocilizumab during Part 1 (Weeks 1 to 52).

    Serious adverse events
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper Part 2: No Tocilizumab (Placebo in Part 1) Part 2: No Tocilizumab (Tocilizumab in Part 1) Part 2: Tocilizumab (Placebo in Part 1) Part 2: Tocilizumab (Tocilizumab in Part 1)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 100 (15.00%)
    7 / 49 (14.29%)
    11 / 50 (22.00%)
    13 / 51 (25.49%)
    7 / 40 (17.50%)
    11 / 58 (18.97%)
    18 / 50 (36.00%)
    23 / 67 (34.33%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    1
    2
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 49 (2.04%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    2 / 50 (4.00%)
    3 / 67 (4.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cancer surgery
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Squamous cell carcinoma of the vulva
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Postoperative wound complication
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cartilage injury
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve stenosis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphocytosis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell disorder
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Nasal inflammation
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    1 / 40 (2.50%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombotic stroke
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    2 / 50 (4.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cartotid artery stenosis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual field defect
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced transiently
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis erosive
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon pain
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Chondropathy
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Genital herpes zoster
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    2 / 50 (4.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis infective
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part 1: Tocilizumab qw + 26 weeks prednisone taper Part 1: Tocilizumab q2w + 26 weeks prednisone taper Part 1: Placebo + 26 weeks prednisone taper Part 1: Placebo + 52 weeks prednisone taper Part 2: No Tocilizumab (Placebo in Part 1) Part 2: No Tocilizumab (Tocilizumab in Part 1) Part 2: Tocilizumab (Placebo in Part 1) Part 2: Tocilizumab (Tocilizumab in Part 1)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    87 / 100 (87.00%)
    44 / 49 (89.80%)
    47 / 50 (94.00%)
    44 / 51 (86.27%)
    33 / 40 (82.50%)
    50 / 58 (86.21%)
    44 / 50 (88.00%)
    61 / 67 (91.04%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    5 / 100 (5.00%)
    3 / 49 (6.12%)
    3 / 50 (6.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    5
    3
    3
    1
    0
    0
    0
    0
    Hypertension
         subjects affected / exposed
    12 / 100 (12.00%)
    6 / 49 (12.24%)
    4 / 50 (8.00%)
    4 / 51 (7.84%)
    1 / 40 (2.50%)
    7 / 58 (12.07%)
    7 / 50 (14.00%)
    8 / 67 (11.94%)
         occurrences all number
    14
    6
    4
    6
    1
    7
    7
    8
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 100 (5.00%)
    3 / 49 (6.12%)
    5 / 50 (10.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    8
    3
    5
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    8 / 100 (8.00%)
    5 / 49 (10.20%)
    8 / 50 (16.00%)
    3 / 51 (5.88%)
    2 / 40 (5.00%)
    2 / 58 (3.45%)
    6 / 50 (12.00%)
    6 / 67 (8.96%)
         occurrences all number
    8
    6
    8
    3
    2
    2
    9
    7
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 49 (4.08%)
    1 / 50 (2.00%)
    3 / 51 (5.88%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    2
    2
    1
    3
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    16 / 100 (16.00%)
    12 / 49 (24.49%)
    8 / 50 (16.00%)
    6 / 51 (11.76%)
    1 / 40 (2.50%)
    2 / 58 (3.45%)
    5 / 50 (10.00%)
    4 / 67 (5.97%)
         occurrences all number
    17
    16
    10
    9
    1
    3
    5
    4
    Discomfort
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    3 / 50 (6.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    2
    Gait disturbance
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 49 (2.04%)
    6 / 50 (12.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    2
    2
    6
    1
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    3 / 100 (3.00%)
    2 / 49 (4.08%)
    3 / 50 (6.00%)
    1 / 51 (1.96%)
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    4 / 50 (8.00%)
    0 / 67 (0.00%)
         occurrences all number
    3
    2
    3
    1
    1
    0
    5
    0
    Insomnia
         subjects affected / exposed
    4 / 100 (4.00%)
    1 / 49 (2.04%)
    4 / 50 (8.00%)
    4 / 51 (7.84%)
    0 / 40 (0.00%)
    2 / 58 (3.45%)
    2 / 50 (4.00%)
    4 / 67 (5.97%)
         occurrences all number
    4
    1
    4
    4
    0
    2
    2
    4
    Sleep disorder
         subjects affected / exposed
    1 / 100 (1.00%)
    3 / 49 (6.12%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    1
    4
    1
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    7 / 100 (7.00%)
    2 / 49 (4.08%)
    2 / 50 (4.00%)
    2 / 51 (3.92%)
    4 / 40 (10.00%)
    2 / 58 (3.45%)
    2 / 50 (4.00%)
    9 / 67 (13.43%)
         occurrences all number
    11
    2
    2
    3
    4
    2
    2
    10
    Arthropod bite
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    1 / 50 (2.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    4
    Limb injury
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    3 / 67 (4.48%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 100 (5.00%)
    2 / 49 (4.08%)
    2 / 50 (4.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    3 / 50 (6.00%)
    0 / 67 (0.00%)
         occurrences all number
    5
    2
    2
    0
    0
    0
    3
    0
    Complement factor C3 decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    4 / 50 (8.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    0
    Complement factor C4 decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    3 / 50 (6.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 49 (4.08%)
    4 / 50 (8.00%)
    2 / 51 (3.92%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    2
    2
    6
    2
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 100 (6.00%)
    3 / 49 (6.12%)
    7 / 50 (14.00%)
    3 / 51 (5.88%)
    2 / 40 (5.00%)
    4 / 58 (6.90%)
    7 / 50 (14.00%)
    4 / 67 (5.97%)
         occurrences all number
    6
    3
    8
    3
    3
    4
    9
    5
    Dyspnoea
         subjects affected / exposed
    3 / 100 (3.00%)
    3 / 49 (6.12%)
    1 / 50 (2.00%)
    3 / 51 (5.88%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    3
    3
    1
    3
    0
    0
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    3 / 50 (6.00%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    0
    3
    0
    Epistaxis
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 49 (2.04%)
    4 / 50 (8.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    4 / 50 (8.00%)
    3 / 67 (4.48%)
         occurrences all number
    3
    1
    4
    0
    0
    0
    5
    4
    Oropharyngeal pain
         subjects affected / exposed
    7 / 100 (7.00%)
    4 / 49 (8.16%)
    4 / 50 (8.00%)
    8 / 51 (15.69%)
    2 / 40 (5.00%)
    2 / 58 (3.45%)
    2 / 50 (4.00%)
    4 / 67 (5.97%)
         occurrences all number
    9
    4
    5
    12
    3
    2
    2
    4
    Dysphonia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    3 / 50 (6.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    Pulmonary mass
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    2 / 40 (5.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    3 / 58 (5.17%)
    1 / 50 (2.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 100 (6.00%)
    10 / 49 (20.41%)
    6 / 50 (12.00%)
    8 / 51 (15.69%)
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    5 / 50 (10.00%)
    4 / 67 (5.97%)
         occurrences all number
    9
    11
    9
    9
    2
    0
    6
    5
    Headache
         subjects affected / exposed
    27 / 100 (27.00%)
    10 / 49 (20.41%)
    16 / 50 (32.00%)
    12 / 51 (23.53%)
    2 / 40 (5.00%)
    8 / 58 (13.79%)
    8 / 50 (16.00%)
    6 / 67 (8.96%)
         occurrences all number
    40
    20
    24
    26
    2
    12
    13
    9
    Paraesthesia
         subjects affected / exposed
    4 / 100 (4.00%)
    2 / 49 (4.08%)
    4 / 50 (8.00%)
    4 / 51 (7.84%)
    0 / 40 (0.00%)
    2 / 58 (3.45%)
    1 / 50 (2.00%)
    5 / 67 (7.46%)
         occurrences all number
    4
    2
    4
    4
    0
    2
    1
    6
    Tremor
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
    3 / 51 (5.88%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    3
    3
    0
    0
    0
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    3 / 50 (6.00%)
    3 / 67 (4.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    3
    3
    Sciatica
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 40 (2.50%)
    2 / 58 (3.45%)
    2 / 50 (4.00%)
    5 / 67 (7.46%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    2
    5
    Syncope
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    2 / 40 (5.00%)
    1 / 58 (1.72%)
    2 / 50 (4.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    2
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    5 / 100 (5.00%)
    1 / 49 (2.04%)
    3 / 50 (6.00%)
    4 / 51 (7.84%)
    2 / 40 (5.00%)
    1 / 58 (1.72%)
    3 / 50 (6.00%)
    3 / 67 (4.48%)
         occurrences all number
    5
    1
    3
    5
    3
    2
    4
    4
    Dry eye
         subjects affected / exposed
    1 / 100 (1.00%)
    3 / 49 (6.12%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    1
    3
    1
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 49 (2.04%)
    3 / 50 (6.00%)
    1 / 51 (1.96%)
    2 / 40 (5.00%)
    2 / 58 (3.45%)
    2 / 50 (4.00%)
    2 / 67 (2.99%)
         occurrences all number
    2
    1
    3
    1
    2
    2
    2
    2
    Tinnitus
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    2 / 50 (4.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 100 (3.00%)
    3 / 49 (6.12%)
    3 / 50 (6.00%)
    4 / 51 (7.84%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    3
    3
    3
    4
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 49 (2.04%)
    3 / 50 (6.00%)
    4 / 51 (7.84%)
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    3 / 50 (6.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    6
    4
    1
    0
    5
    1
    Diarrhoea
         subjects affected / exposed
    12 / 100 (12.00%)
    3 / 49 (6.12%)
    8 / 50 (16.00%)
    5 / 51 (9.80%)
    2 / 40 (5.00%)
    2 / 58 (3.45%)
    7 / 50 (14.00%)
    5 / 67 (7.46%)
         occurrences all number
    13
    3
    12
    6
    3
    2
    15
    8
    Dyspepsia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    4 / 50 (8.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    2 / 58 (3.45%)
    3 / 50 (6.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    5
    1
    0
    2
    3
    0
    Nausea
         subjects affected / exposed
    8 / 100 (8.00%)
    2 / 49 (4.08%)
    5 / 50 (10.00%)
    4 / 51 (7.84%)
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    5 / 50 (10.00%)
    3 / 67 (4.48%)
         occurrences all number
    11
    2
    7
    5
    2
    0
    7
    4
    Vomiting
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 49 (4.08%)
    2 / 50 (4.00%)
    3 / 51 (5.88%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    2
    2
    3
    3
    0
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    2 / 40 (5.00%)
    1 / 58 (1.72%)
    0 / 50 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    1
    Toothache
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    5 / 67 (7.46%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 100 (5.00%)
    7 / 49 (14.29%)
    3 / 50 (6.00%)
    5 / 51 (9.80%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    4 / 50 (8.00%)
    2 / 67 (2.99%)
         occurrences all number
    5
    7
    3
    5
    0
    0
    4
    2
    Dry skin
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 49 (6.12%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    2
    4
    0
    0
    0
    0
    0
    0
    Ecchymosis
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 49 (4.08%)
    1 / 50 (2.00%)
    3 / 51 (5.88%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    2
    1
    4
    0
    0
    0
    0
    Night sweats
         subjects affected / exposed
    1 / 100 (1.00%)
    3 / 49 (6.12%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    2 / 58 (3.45%)
    1 / 50 (2.00%)
    4 / 67 (5.97%)
         occurrences all number
    1
    3
    1
    1
    0
    2
    1
    4
    Pruritus
         subjects affected / exposed
    2 / 100 (2.00%)
    4 / 49 (8.16%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    2
    4
    1
    1
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    7 / 100 (7.00%)
    5 / 49 (10.20%)
    4 / 50 (8.00%)
    2 / 51 (3.92%)
    2 / 40 (5.00%)
    2 / 58 (3.45%)
    0 / 50 (0.00%)
    5 / 67 (7.46%)
         occurrences all number
    7
    5
    7
    2
    2
    2
    0
    7
    Eczema
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 40 (2.50%)
    3 / 58 (5.17%)
    2 / 50 (4.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    1
    4
    23
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 100 (13.00%)
    8 / 49 (16.33%)
    10 / 50 (20.00%)
    8 / 51 (15.69%)
    7 / 40 (17.50%)
    10 / 58 (17.24%)
    10 / 50 (20.00%)
    12 / 67 (17.91%)
         occurrences all number
    13
    10
    11
    11
    9
    15
    13
    18
    Back pain
         subjects affected / exposed
    14 / 100 (14.00%)
    7 / 49 (14.29%)
    7 / 50 (14.00%)
    10 / 51 (19.61%)
    3 / 40 (7.50%)
    4 / 58 (6.90%)
    8 / 50 (16.00%)
    7 / 67 (10.45%)
         occurrences all number
    16
    14
    8
    12
    3
    5
    10
    7
    Bursitis
         subjects affected / exposed
    1 / 100 (1.00%)
    4 / 49 (8.16%)
    2 / 50 (4.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    1
    4
    2
    1
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    4 / 100 (4.00%)
    6 / 49 (12.24%)
    6 / 50 (12.00%)
    4 / 51 (7.84%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    5 / 50 (10.00%)
    6 / 67 (8.96%)
         occurrences all number
    4
    9
    6
    6
    0
    0
    7
    6
    Musculoskeletal pain
         subjects affected / exposed
    12 / 100 (12.00%)
    6 / 49 (12.24%)
    5 / 50 (10.00%)
    2 / 51 (3.92%)
    4 / 40 (10.00%)
    6 / 58 (10.34%)
    4 / 50 (8.00%)
    4 / 67 (5.97%)
         occurrences all number
    13
    7
    7
    2
    4
    6
    4
    4
    Myalgia
         subjects affected / exposed
    9 / 100 (9.00%)
    4 / 49 (8.16%)
    4 / 50 (8.00%)
    4 / 51 (7.84%)
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    3 / 50 (6.00%)
    2 / 67 (2.99%)
         occurrences all number
    9
    4
    5
    5
    1
    0
    3
    2
    Neck pain
         subjects affected / exposed
    6 / 100 (6.00%)
    1 / 49 (2.04%)
    2 / 50 (4.00%)
    4 / 51 (7.84%)
    2 / 40 (5.00%)
    1 / 58 (1.72%)
    3 / 50 (6.00%)
    1 / 67 (1.49%)
         occurrences all number
    7
    1
    3
    4
    2
    1
    4
    1
    Osteoarthritis
         subjects affected / exposed
    7 / 100 (7.00%)
    2 / 49 (4.08%)
    3 / 50 (6.00%)
    3 / 51 (5.88%)
    1 / 40 (2.50%)
    2 / 58 (3.45%)
    6 / 50 (12.00%)
    6 / 67 (8.96%)
         occurrences all number
    7
    3
    3
    3
    1
    2
    9
    8
    Pain in extremity
         subjects affected / exposed
    8 / 100 (8.00%)
    5 / 49 (10.20%)
    5 / 50 (10.00%)
    5 / 51 (9.80%)
    1 / 40 (2.50%)
    5 / 58 (8.62%)
    4 / 50 (8.00%)
    7 / 67 (10.45%)
         occurrences all number
    8
    7
    5
    7
    1
    5
    6
    11
    Osteopenia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 40 (0.00%)
    3 / 58 (5.17%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 40 (2.50%)
    2 / 58 (3.45%)
    5 / 50 (10.00%)
    3 / 67 (4.48%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    5
    3
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 49 (6.12%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    2 / 58 (3.45%)
    1 / 50 (2.00%)
    5 / 67 (7.46%)
         occurrences all number
    2
    3
    0
    1
    0
    2
    1
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 100 (8.00%)
    4 / 49 (8.16%)
    5 / 50 (10.00%)
    5 / 51 (9.80%)
    4 / 40 (10.00%)
    9 / 58 (15.52%)
    3 / 50 (6.00%)
    9 / 67 (13.43%)
         occurrences all number
    9
    4
    5
    5
    4
    13
    4
    9
    Conjunctivitis
         subjects affected / exposed
    4 / 100 (4.00%)
    1 / 49 (2.04%)
    4 / 50 (8.00%)
    1 / 51 (1.96%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    4 / 50 (8.00%)
    3 / 67 (4.48%)
         occurrences all number
    5
    1
    4
    1
    0
    0
    5
    4
    Cystitis
         subjects affected / exposed
    7 / 100 (7.00%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
    3 / 51 (5.88%)
    2 / 40 (5.00%)
    3 / 58 (5.17%)
    4 / 50 (8.00%)
    3 / 67 (4.48%)
         occurrences all number
    13
    0
    4
    8
    3
    5
    21
    17
    Gastroenteritis
         subjects affected / exposed
    3 / 100 (3.00%)
    4 / 49 (8.16%)
    4 / 50 (8.00%)
    3 / 51 (5.88%)
    0 / 40 (0.00%)
    2 / 58 (3.45%)
    3 / 50 (6.00%)
    4 / 67 (5.97%)
         occurrences all number
    3
    4
    4
    4
    0
    2
    3
    4
    Nasopharyngitis
         subjects affected / exposed
    29 / 100 (29.00%)
    12 / 49 (24.49%)
    9 / 50 (18.00%)
    13 / 51 (25.49%)
    5 / 40 (12.50%)
    13 / 58 (22.41%)
    14 / 50 (28.00%)
    22 / 67 (32.84%)
         occurrences all number
    39
    15
    12
    17
    9
    15
    20
    36
    Oral herpes
         subjects affected / exposed
    4 / 100 (4.00%)
    5 / 49 (10.20%)
    3 / 50 (6.00%)
    2 / 51 (3.92%)
    2 / 40 (5.00%)
    2 / 58 (3.45%)
    1 / 50 (2.00%)
    2 / 67 (2.99%)
         occurrences all number
    4
    5
    3
    2
    2
    2
    1
    2
    Pharyngitis
         subjects affected / exposed
    4 / 100 (4.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    3 / 51 (5.88%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    4
    0
    1
    3
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    6 / 100 (6.00%)
    4 / 49 (8.16%)
    2 / 50 (4.00%)
    3 / 51 (5.88%)
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 50 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    6
    4
    2
    3
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    3 / 100 (3.00%)
    4 / 49 (8.16%)
    1 / 50 (2.00%)
    2 / 51 (3.92%)
    2 / 40 (5.00%)
    1 / 58 (1.72%)
    1 / 50 (2.00%)
    6 / 67 (8.96%)
         occurrences all number
    4
    4
    1
    2
    2
    1
    1
    10
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 100 (10.00%)
    6 / 49 (12.24%)
    5 / 50 (10.00%)
    7 / 51 (13.73%)
    1 / 40 (2.50%)
    2 / 58 (3.45%)
    7 / 50 (14.00%)
    2 / 67 (2.99%)
         occurrences all number
    10
    7
    5
    9
    1
    3
    8
    3
    Urinary tract infection
         subjects affected / exposed
    10 / 100 (10.00%)
    4 / 49 (8.16%)
    2 / 50 (4.00%)
    4 / 51 (7.84%)
    1 / 40 (2.50%)
    4 / 58 (6.90%)
    10 / 50 (20.00%)
    10 / 67 (14.93%)
         occurrences all number
    15
    5
    4
    7
    1
    4
    19
    15
    Herpes zoster
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 40 (2.50%)
    4 / 58 (6.90%)
    4 / 50 (8.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    0
    0
    0
    1
    4
    4
    2
    Influenza
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 40 (2.50%)
    2 / 58 (3.45%)
    3 / 50 (6.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    3
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    1 / 50 (2.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    2
    Respiratory tract infection
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    4 / 40 (10.00%)
    2 / 58 (3.45%)
    1 / 50 (2.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    0
    0
    5
    2
    1
    4

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2012
    The inclusion criteria related to the requirement for a history of ESR >/=50 mm/hr and active disease according to an ESR >/=30 mm/hr were clarified; The exclusion criteria were revised to exclude only major ischemic events unrelated to GCA and a new exclusion criterion added to exclude participants who received pulsed methylprednisolone within 6 weeks of baseline; The criteria concerning re-screening and retesting for laboratory inclusion/exclusion criteria were outlined; The definition of remission was clarified; All participants were made eligible for transition from Part 1 to Part 2 of the study; The status of prednisone as an investigational medicinal product (IMP) during Part 1 of the study was clarified; The protocol was aligned with the Sponsor’s memorandum on “Implementing immunoglobulin (Ig)E Assay for tocilizumab Immunogenicity Testing” and immunogenicity testing for participants who discontinued treatment with tocilizumab was added; Collection of information on prior medications and electrocardiograms (ECGs) was simplified; Visit windows were revised to increase flexibility and participant retention; Collection of laboratory assessments was clarified; Information on tocilizumab syringe labels was standardized with that of drug supply; Lipid-lowering agents were added to the list of permitted concomitant non-investigational medicinal products (NIMPs).
    08 Feb 2013
    Following Food and Drug Administration (FDA) feedback the definition of relapsing participants was updated to include those with active disease despite at least 2 consecutive weeks of treatment with >/=40 mg/day prednisone (or equivalent) at any time; Following FDA feedback the key secondary endpoint defining a comparison of the proportion of participants in sustained remission at Week 52 in the tocilizumab groups versus the placebo group with 52-week prednisone taper was added; The terminology of the dual assessors was changed; Addition of a ribonucleic acid (RNA) blood sample and serum sample for biomarkers at unscheduled visit; Addition of an exclusion criterion specifying that previous treatment with tofacitinib was not permitted; Timing of the collection of the immunogenicity samples was amended.
    22 Jan 2014
    To better reflect clinical practice where CRP is replacing ESR in several health centers, the requirement for a CRP >/=2.45 mg/dL for participants where a historical ESR value was unavailable was added; Removal of the requirement of ESR >/=30 mm/hr or CRP >/=1 mg/dL to confirm active disease in participants with a positive temporal artery biopsy within 6 weeks of baseline; Definition of flare was modified to allow the clinical assessor to consider an elevated ESR as disease flare in the absence of GCA signs and symptoms if, in their opinion, it was attributable to GCA; Further clarification of the definition of new-onset GCA was made; Clarification to the concomitant