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    Clinical Trial Results:
    A Randomized, Phase 3, Controlled, Double-Blind, Parallel-Group, Multicenter Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate (MTX) Compared to MTX Alone, in Methotrexate-Naive Patients With Active Rheumatoid Arthritis

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2005-002395-15
    Trial protocol
    FI   ES   DE   BE   SE   CZ   IT   GB   DK  
    Global end of trial date
    22 Jul 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    15 Jul 2016
    First version publication date
    07 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Due to EMA system issues, the record results need correction by the MAH.

    Trial information

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    Trial identification
    Sponsor protocol code
    WA17047
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00299104
    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 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 616878333, 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
    22 Jul 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of rituximab in the prevention of progression in structural joint damage and to evaluate the safety of rituximab in participants with active rheumatoid arthritis initiating treatment with MTX.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Jan 2006
    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
    United States: 181
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czech Republic: 21
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 42
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Brazil: 43
    Country: Number of subjects enrolled
    Canada: 29
    Country: Number of subjects enrolled
    China: 36
    Country: Number of subjects enrolled
    Guatemala: 22
    Country: Number of subjects enrolled
    India: 35
    Country: Number of subjects enrolled
    Mexico: 65
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Panama: 10
    Country: Number of subjects enrolled
    Peru: 34
    Country: Number of subjects enrolled
    Philippines: 17
    Country: Number of subjects enrolled
    Poland: 54
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Korea, Republic of: 18
    Worldwide total number of subjects
    748
    EEA total number of subjects
    241
    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)
    668
    From 65 to 84 years
    80
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Screening was from Day -28 to Day 1 which could be extended to accommodate washout of prohibited medications. Participants randomized to the study were 251, 252 and 252 in placebo+methotrexate arm, rituximab(0.5 g x 2) + methotrexate and rituximab(1.0 g x 2) + methotrexate, respectively, out of which 748 received study drug.

    Period 1
    Period 1 title
    Treatment Phase
    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
    Placebo Plus (+) Methotrexate
    Arm description
    Placebo intravenously on Days 1 and 15 + methotrexate orally at a dose of 7.5 milligrams (mg) escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. From Week 104 participants were eligible to receive Rituximab 2 X 0.5 grams (g) or Rituximab 2 X 1.0 g every 24 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received placebo intravenously on Days 1 and 15.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received either 0.5 mg or 1.0 mg rituximab intravenously on Days 1 and 15.

    Arm title
    Rituximab (0.5 g X 2) + Methotrexate
    Arm description
    Rituximab intravenously at a dose of 0.5 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS-ESR) result was greater than or equal to (≥)2.6.
    Arm type
    Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received rituximab intravenously at a dose of 0.5 g on Days 1 and 15. Subsequent rituximab courses were given every 24 weeks for up to 5 years, as indicated.

    Arm title
    Rituximab (1.0 g x 2) + Methotrexate
    Arm description
    Rituximab intravenously at a dose of 1.0 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the DAS-ESR result was ≥2.6.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1.0 mg intravenously on Days 1 and 15. Subsequent treatment courses were given every 24 weeks up to 5 years, as indicated.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    7.5 mg escalating by 2.5 mg a week ever 1-2 weeks to achieve 15 mg per week by week 4 and 20 mg per week by Week 8.

    Number of subjects in period 1
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Started
    249
    249
    250
    Safety/ITT: Received Study Drug
    249
    249
    250
    Completed Week 24
    227
    240
    241
    Completed Week 52
    213
    227
    232
    Completed Week 104
    178
    213
    216
    Completed
    62
    77
    80
    Not completed
    187
    172
    170
         Protocol deviation
    1
    1
    -
         Death
    1
    1
    1
         Refused treatment
    9
    2
    2
         Adverse event
    14
    9
    7
         Violation of selection criteria
    1
    2
    -
         Insufficient therapeutic response
    34
    13
    8
         Consent withdrawn by subject
    14
    19
    9
         Administrative reasons
    104
    117
    135
         Lost to follow-up
    9
    8
    8
    Period 2
    Period 2 title
    Safety Follow-Up (SFU)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SFU: Placebo + Methotrexate
    Arm description
    At the end of 3 year treatment period participants were followed for a 48-Week Safety Follow-Up. During the SFU period no further study drug was administered.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    SFU: Rituximab (0.5 g x 2) + Methotrexate
    Arm description
    At the end of 3 year treatment period participants were followed for a 48-Week Safety Follow-Up. During the SFU period no further study drug was administered.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    SFU: Rituximab (1.0 g x 2) + Methotrexate
    Arm description
    At the end of 3 year treatment period participants were followed for a 48-Week Safety Follow-Up. During the SFU period no further study drug was administered.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    SFU: Placebo + Methotrexate SFU: Rituximab (0.5 g x 2) + Methotrexate SFU: Rituximab (1.0 g x 2) + Methotrexate
    Started
    62
    77
    80
    Entered Extended Safety Follow-Up
    129
    40
    51
    Completed
    129
    171
    176
    Not completed
    55
    41
    37
         Death
    3
    2
    1
         Failure to return
    -
    11
    20
         Consent withdrawn by subject
    16
    21
    11
         Administrative reasons
    27
    7
    5
         Lost to follow-up
    9
    -
    -
    Joined
    122
    135
    133
         Entered Safety Follow-Up
    122
    -
    -
         Completed Week 104 of Treatment Phase
    -
    135
    133
    Period 3
    Period 3 title
    Extended Safety Follow-Up (ESFU) Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ESFU: Placebo + Methotrexate
    Arm description
    At the end of 48-Week SFU participants entered ESFU. Participants who did not receive any study drug were not required to enter ESFU for a period of additional 48 weeks. During the ESFU period no further study drug was administered.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    ESFU: Rituximab (0.5 g x 2) + Methotrexate
    Arm description
    At the end of 48-Week SFU participants entered ESFU. Only participants who received the study drug entered ESFU for a period of additional 48 weeks. During the ESFU period no further study drug was administered.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    ESFU: Rituximab (1.0 g x 2) + Methotrexate
    Arm description
    At the end of 48-Week SFU participants entered ESFU. Only participants who received the study drug entered ESFU for a period of additional 48 weeks. During the ESFU period no further study drug was administered.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3 [1]
    ESFU: Placebo + Methotrexate ESFU: Rituximab (0.5 g x 2) + Methotrexate ESFU: Rituximab (1.0 g x 2) + Methotrexate
    Started
    34
    40
    51
    Completed
    29
    31
    39
    Not completed
    5
    9
    12
         Death
    -
    1
    -
         Consent withdrawn by subject
    2
    4
    8
         Administrative reasons
    1
    2
    2
         Lost to follow-up
    2
    2
    2
    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: Only participants with CD19+ B-cell counts below baseline level or less than 80 cells/microliter entered the ESFU period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo Plus (+) Methotrexate
    Reporting group description
    Placebo intravenously on Days 1 and 15 + methotrexate orally at a dose of 7.5 milligrams (mg) escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. From Week 104 participants were eligible to receive Rituximab 2 X 0.5 grams (g) or Rituximab 2 X 1.0 g every 24 weeks.

    Reporting group title
    Rituximab (0.5 g X 2) + Methotrexate
    Reporting group description
    Rituximab intravenously at a dose of 0.5 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS-ESR) result was greater than or equal to (≥)2.6.

    Reporting group title
    Rituximab (1.0 g x 2) + Methotrexate
    Reporting group description
    Rituximab intravenously at a dose of 1.0 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the DAS-ESR result was ≥2.6.

    Reporting group values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate Total
    Number of subjects
    249 249 250 748
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    48.06 ± 12.692 47.87 ± 13.391 47.89 ± 13.324 -
    Gender categorical
    Units: Subjects
        Female
    192 203 212 607
        Male
    57 46 38 141

    End points

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    End points reporting groups
    Reporting group title
    Placebo Plus (+) Methotrexate
    Reporting group description
    Placebo intravenously on Days 1 and 15 + methotrexate orally at a dose of 7.5 milligrams (mg) escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. From Week 104 participants were eligible to receive Rituximab 2 X 0.5 grams (g) or Rituximab 2 X 1.0 g every 24 weeks.

    Reporting group title
    Rituximab (0.5 g X 2) + Methotrexate
    Reporting group description
    Rituximab intravenously at a dose of 0.5 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS-ESR) result was greater than or equal to (≥)2.6.

    Reporting group title
    Rituximab (1.0 g x 2) + Methotrexate
    Reporting group description
    Rituximab intravenously at a dose of 1.0 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the DAS-ESR result was ≥2.6.
    Reporting group title
    SFU: Placebo + Methotrexate
    Reporting group description
    At the end of 3 year treatment period participants were followed for a 48-Week Safety Follow-Up. During the SFU period no further study drug was administered.

    Reporting group title
    SFU: Rituximab (0.5 g x 2) + Methotrexate
    Reporting group description
    At the end of 3 year treatment period participants were followed for a 48-Week Safety Follow-Up. During the SFU period no further study drug was administered.

    Reporting group title
    SFU: Rituximab (1.0 g x 2) + Methotrexate
    Reporting group description
    At the end of 3 year treatment period participants were followed for a 48-Week Safety Follow-Up. During the SFU period no further study drug was administered.
    Reporting group title
    ESFU: Placebo + Methotrexate
    Reporting group description
    At the end of 48-Week SFU participants entered ESFU. Participants who did not receive any study drug were not required to enter ESFU for a period of additional 48 weeks. During the ESFU period no further study drug was administered.

    Reporting group title
    ESFU: Rituximab (0.5 g x 2) + Methotrexate
    Reporting group description
    At the end of 48-Week SFU participants entered ESFU. Only participants who received the study drug entered ESFU for a period of additional 48 weeks. During the ESFU period no further study drug was administered.

    Reporting group title
    ESFU: Rituximab (1.0 g x 2) + Methotrexate
    Reporting group description
    At the end of 48-Week SFU participants entered ESFU. Only participants who received the study drug entered ESFU for a period of additional 48 weeks. During the ESFU period no further study drug was administered.

    Primary: Change From Baseline in Modified Total Sharp Score (mTSS) From Screening at Week 52

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    End point title
    Change From Baseline in Modified Total Sharp Score (mTSS) From Screening at Week 52
    End point description
    Rate of progression in structural joint damage (PJD) by change in Total Modified Sharp Score (TMSS) from screening to Week 52 in the modified intent-to-treat (MITT) population. MITT population included all randomized participants who received at least one infusion and had both screening and post-baseline radiographic assessments at the given time-point for analysis. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing. Modified intent-to-treat (MITT) population includes patients with a screening and at least one post-baseline radiographic evaluation, grouped as randomized. Linear interpolation/extrapolation used for missing data.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    232 [1]
    239 [2]
    244 [3]
    Units: score on a scale
        arithmetic mean (standard deviation)
    1.079 ± 4.0934
    0.646 ± 1.9196
    0.359 ± 1.0095
    Notes
    [1] - MITT population
    [2] - MITT population
    [3] - MITT population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Comparing all three treatment groups. The Closure Principle was used to adjust for multiple comparisons.
    Comparison groups
    Placebo Plus (+) Methotrexate v Rituximab (0.5 g X 2) + Methotrexate v Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects included in analysis
    715
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0016
    Method
    Kruskal-wallis
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Rituximab 2 x 0.5 g + Methotrexate arm versus (vs) Placebo + Methotrexate, stratified for region and baseline rheumatoid factor (RF) status. The Closure Principle was used to adjust for multiple comparisons.
    Comparison groups
    Placebo Plus (+) Methotrexate v Rituximab (0.5 g X 2) + Methotrexate
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1824
    Method
    Van-Elteren
    Confidence interval
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Rituximab 2 x 1.0 g + Methotrexate arm vs Placebo + Methotrexate, stratified for region and baseline RF status. The Closure Principle was used to adjust for multiple comparisons.
    Comparison groups
    Placebo Plus (+) Methotrexate v Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0004
    Method
    Van-Elteren
    Confidence interval

    Secondary: Change From Baseline in Modified Sharp Erosion Score at Week 52

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    End point title
    Change From Baseline in Modified Sharp Erosion Score at Week 52
    End point description
    Rate of PJD by change in modified Sharp erosion score from screening to Week 52. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    232 [4]
    239 [5]
    244 [6]
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.738 ± 2.048
    0.453 ± 1.2065
    0.233 ± 0.6252
    Notes
    [4] - MITT population
    [5] - MITT population
    [6] - MITT population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Comparing all three treatment groups; The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.
    Comparison groups
    Placebo Plus (+) Methotrexate v Rituximab (0.5 g X 2) + Methotrexate v Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects included in analysis
    715
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0004
    Method
    Kruskal-wallis
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Rituximab 2 x 0.5 g + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status. The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.
    Comparison groups
    Rituximab (0.5 g X 2) + Methotrexate v Placebo Plus (+) Methotrexate
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1194
    Method
    Van-Elteren
    Confidence interval
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Rituximab 2 x 1.0 g + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status. The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.
    Comparison groups
    Placebo Plus (+) Methotrexate v Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0001
    Method
    Van-Elteren
    Confidence interval

    Secondary: Percentage of Participants Without Radiographic Progression at Week 52

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    End point title
    Percentage of Participants Without Radiographic Progression at Week 52
    End point description
    Percentage of participants without radiographic progression at Week 52, defined as change in total modified Sharp Score (TMSS) ≤ 0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    232 [7]
    239 [8]
    244 [9]
    Units: Percentage
        number (not applicable)
    53.4
    57.7
    63.5
    Notes
    [7] - MITT population
    [8] - MITT population
    [9] - MITT population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
    Comparison groups
    Placebo Plus (+) Methotrexate v Rituximab (0.5 g X 2) + Methotrexate
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3803 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.05
         upper limit
    0.13
    Notes
    [10] - This was a secondary endpoint in a hierarchical testing structure.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Rituximab (1.0 g x 2) + Methotrexate v Placebo Plus (+) Methotrexate
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0309 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    0.18
    Notes
    [11] - This was a secondary endpoint in a hierarchical testing structure.

    Secondary: Percentage of Participants Without Radiographic Progression in Total Erosion Score at Week 52

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    End point title
    Percentage of Participants Without Radiographic Progression in Total Erosion Score at Week 52
    End point description
    No radiographic progression is defined as a change in the total erosion score at Week 52 of less than or equal to zero.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    232 [12]
    239 [13]
    244 [14]
    Units: Percentage of participants
        number (not applicable)
    54.7
    59
    66.8
    Notes
    [12] - MITT population
    [13] - MITT population
    [14] - MITT population
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Rituximab (0.5 g X 2) + Methotrexate v Placebo Plus (+) Methotrexate
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    P-value
    = 0.3752 [16]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [15] - Rituximab (0.5 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.
    [16] - This was a secondary endpoint in a hierarchical testing structure.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Rituximab (1.0 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and Baseline RF status.
    Comparison groups
    Rituximab (1.0 g x 2) + Methotrexate v Placebo Plus (+) Methotrexate
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0081 [17]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [17] - This was a secondary endpoint in a hierarchical testing structure.

    Secondary: Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 52

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    End point title
    Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 52
    End point description
    Rate of progression in structural joint damage (PJD) by change in modified joint space narrowing (JSN) from screening to Week 52. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint space narrowing.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    232 [18]
    239 [19]
    244 [20]
    Units: Units on a scale
        arithmetic mean (standard deviation)
    0.341 ± 2.2408
    0.193 ± 0.9422
    0.126 ± 0.6363
    Notes
    [18] - MITT population
    [19] - MITT population
    [20] - MITT population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Comparing all three treatment groups
    Comparison groups
    Placebo Plus (+) Methotrexate v Rituximab (0.5 g X 2) + Methotrexate v Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects included in analysis
    715
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5939 [21]
    Method
    Kruskal-wallis
    Confidence interval
    Notes
    [21] - The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
    Comparison groups
    Rituximab (0.5 g X 2) + Methotrexate v Placebo Plus (+) Methotrexate
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5478 [22]
    Method
    Van-Elteren
    Confidence interval
    Notes
    [22] - The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Rituximab 2 x 1.0 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
    Comparison groups
    Rituximab (1.0 g x 2) + Methotrexate v Placebo Plus (+) Methotrexate
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3096 [23]
    Method
    Van-Elteren
    Confidence interval
    Notes
    [23] - The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.

    Secondary: Change From Baseline in the Modified Total Sharp Score at Week 24

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    End point title
    Change From Baseline in the Modified Total Sharp Score at Week 24
    End point description
    The modified Total Sharp Score is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    226 [24]
    238 [25]
    242 [26]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.701 ± 2.9116
    0.508 ± 1.7349
    0.328 ± 0.9443
    Notes
    [24] - MITT population
    [25] - MITT population
    [26] - MITT population
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Total Erosion Score at Week 24

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    End point title
    Change From Baseline in the Total Erosion Score at Week 24
    End point description
    Total Erosion Score is determined by evaluation of fourteen sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces. The Total Erosion Score at Week 24 - Total Erosion Score at baseline is calculated.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    226
    238
    242
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.491 ± 1.3789
    0.404 ± 1.039
    0.22 ± 0.5802
    No statistical analyses for this end point

    Secondary: Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 24

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    End point title
    Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 24
    End point description
    Joint Space Narrowing is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint space narrowing.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    226 [27]
    238 [28]
    242 [29]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.21 ± 1.7403
    0.176 ± 0.8949
    0.108 ± 0.6118
    Notes
    [27] - MITT population
    [28] - MITT population
    [29] - MITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants Without Radiographic Progression at Week 24

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    End point title
    Percentage of Participants Without Radiographic Progression at Week 24
    End point description
    Percentage of participants without radiographic progression at Week 24 defined as change in total modified Sharp score (TMSS) ≤ 0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    233
    239
    244
    Units: Percentage of participants
        number (not applicable)
    59.7
    65.3
    71.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants With American College of Rheumatology (ACR) ACR50 Response at Week 52

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    End point title
    Percentage of Participants With American College of Rheumatology (ACR) ACR50 Response at Week 52
    End point description
    To achieve an ACR50 response requires at least a 50% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 50% improvement in three of five additional measurements from: The physician's global assessment of disease activity; Patient's global assessment of disease activity; Patient's assessment of pain; HAQ-DI (Health Assessment Questionnaire disability index); Intent to treat (ITT) population includes all randomized participants who received at least one infusion. Patients are considered non-responders if data are missing or from the point of withdrawal, rescue use or receipt of non-permitted Disease-modifying anti-rheumatic drugs (DMARDs).
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    249 [30]
    249 [31]
    250 [32]
    Units: Percentage of participants
        number (not applicable)
    41.8
    59.4
    64.8
    Notes
    [30] - ITT population
    [31] - ITT population
    [32] - ITT population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
    Comparison groups
    Placebo Plus (+) Methotrexate v Rituximab (0.5 g X 2) + Methotrexate
    Number of subjects included in analysis
    498
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [33]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [33] - This was a secondary endpoint in a hierarchical testing structure.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Rituximab 2 x 1.0 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
    Comparison groups
    Rituximab (1.0 g x 2) + Methotrexate v Placebo Plus (+) Methotrexate
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [34]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [34] - This was a secondary endpoint in a hierarchical testing structure.

    Secondary: Change From Baseline in the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 52

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    End point title
    Change From Baseline in the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 52
    End point description
    DAS28-ESR is calculated from the following formula: (0.56 * TJC) + (0.28 * SJC) + (0.70 * ln ESR) + (0.014 * GH) TJC = tender joint count, based on 28 joints SJC = swollen joint count, based on 28 joints ESR = erythrocyte sedimentation rate in millimeters per hour (mm/h) GH = patient's global assessment of disease activity A DAS28-ESR score of 5.1 or above is considered to indicate high disease activity. Participants can also be defined as having low disease activity (DAS28-ESR ≤ 3.2) or remission (DAS28-ESR < 2.6).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    244 [35]
    247 [36]
    248 [37]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -2.33 ± 1.691
    -3.35 ± 1.663
    -3.46 ± 1.64
    Notes
    [35] - ITT population
    [36] - ITT population
    [37] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With American College of Rheumatology (ACR) ACR70 Response at Week 52

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    End point title
    Percentage of Participants With American College of Rheumatology (ACR) ACR70 Response at Week 52
    End point description
    To achieve an ACR70 response requires at least a 70% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 70% improvement in three of five additional measurements from: The physician's global assessment of disease activity; Patient's global assessment of disease activity; Patient's assessment of pain; HAQ-DI (Health Assessment Questionnaire disability index); An acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.);
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    249 [38]
    249 [39]
    250 [40]
    Units: Percentage of participants
        number (not applicable)
    24.9
    42.2
    46.8
    Notes
    [38] - ITT population
    [39] - ITT population
    [40] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With DAS28-ESR Remission at Week 52

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    End point title
    Percentage of Participants With DAS28-ESR Remission at Week 52
    End point description
    The DAS28-4(ESR) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity (mm), and ESR. DAS28-4(ESR) scores range from 0 - 10. Remission is defined as achieving a DAS28-ESR score of less than 2.6
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    247 [41]
    248 [42]
    249 [43]
    Units: Percentage of participants
        number (not applicable)
    12.6
    25.4
    30.5
    Notes
    [41] - ITT population
    [42] - ITT population
    [43] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With European League Against Rheumatism (EULAR) Good Response at Week 52

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    End point title
    Percentage of Participants With European League Against Rheumatism (EULAR) Good Response at Week 52
    End point description
    European League Against Rheumatism (EULAR) criteria reflects an improvement in disease activity and an attainment of a lower degree of disease activity. A good response is defined as an improvement in the DAS28-ESR of >1.2 compared with baseline, and attainment of a DAS28-ESR of <3.2.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    249 [44]
    249 [45]
    250 [46]
    Units: Percentage of participants
        number (not applicable)
    18.1
    39
    41.6
    Notes
    [44] - ITT population
    [45] - ITT population
    [46] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Major Clinical Response at Week 52

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    End point title
    Percentage of Participants With Major Clinical Response at Week 52
    End point description
    Major clinical response is defined as a continuous six-month period of success by the ACR70. ACR70= 70% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 70% improvement in 3 of five additional measurements from: The physician's global assessment of disease activity; Patient's global assessment of disease activity; Patient's assessment of pain HAQ-DI (Health Assessment Questionnaire disability index) An acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    249 [47]
    249 [48]
    250 [49]
    Units: Percentage of participants
        number (not applicable)
    8.4
    18.1
    21.2
    Notes
    [47] - ITT population
    [48] - ITT population
    [49] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With DAS28-ESR Low Disease Activity at Week 52

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    End point title
    Percentage of Participants With DAS28-ESR Low Disease Activity at Week 52
    End point description
    The DAS28-4(ESR) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity (mm), and ESR. DAS28-4(ESR) scores range from 0 - 10. Low disease activity is defined as achieving a DAS28-ESR score of less than or equal to 3.2
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    247 [50]
    248 [51]
    249 [52]
    Units: Percentage of participants
        number (not applicable)
    19.8
    40.3
    43
    Notes
    [50] - ITT population
    [51] - ITT population
    [52] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With American College of Rheumatology (ACR) ACR20 Response at Week 52

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    End point title
    Percentage of Participants With American College of Rheumatology (ACR) ACR20 Response at Week 52
    End point description
    To achieve an ACR20 response requires at least a 20% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 20% improvement in three of five additional measurements from: The physician's global assessment of disease activity; Patient's global assessment of disease activity; Patient's assessment of pain; HAQ-DI (Health Assessment Questionnaire disability index); An acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    249 [53]
    249 [54]
    250 [55]
    Units: Percentage of participants
        number (not applicable)
    64.3
    76.7
    80
    Notes
    [53] - ITT population
    [54] - ITT population
    [55] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With American College of Rheumatology (ACR) ACR90 Response at Week 52

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    End point title
    Percentage of Participants With American College of Rheumatology (ACR) ACR90 Response at Week 52
    End point description
    To achieve an ACR90 response requires at least a 90% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 90% improvement in three of five additional measurements from: The physician's global assessment of disease activity patient's global assessment of disease activity; Patient's assessment of pain; HAQ-DI (Health Assessment Questionnaire disability index); An acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    249 [56]
    249 [57]
    250 [58]
    Units: Percentage of participants
        number (not applicable)
    9.2
    17.3
    16.4
    Notes
    [56] - ITT population
    [57] - ITT population
    [58] - ITT population
    No statistical analyses for this end point

    Secondary: Change in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score From Baseline at Week 52

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    End point title
    Change in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score From Baseline at Week 52
    End point description
    FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the Participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the participant's health status.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    198 [59]
    206 [60]
    218 [61]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    10.154 ± 11.1344
    11.833 ± 11.5807
    12.426 ± 12.2535
    Notes
    [59] - ITT population
    [60] - ITT population
    [61] - ITT population
    No statistical analyses for this end point

    Secondary: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52

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    End point title
    Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52
    End point description
    The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a participant completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip,and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do).HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    248 [62]
    247 [63]
    249 [64]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.8 ± 0.7764
    -1.038 ± 0.7625
    -1.023 ± 0.7634
    Notes
    [62] - ITT population
    [63] - ITT population
    [64] - ITT population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Rituximab (0.5 g x 2) + Methotrexate versus Placebo + Methotrexate stratified for region and RF status.
    Comparison groups
    Placebo Plus (+) Methotrexate v Rituximab (0.5 g X 2) + Methotrexate
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [65]
    Method
    ANOVA
    Confidence interval
    Notes
    [65] - Secondary endpoint in hierarchical testing structure.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Rituximab (1.0 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.
    Comparison groups
    Rituximab (1.0 g x 2) + Methotrexate v Placebo Plus (+) Methotrexate
    Number of subjects included in analysis
    497
    Analysis specification
    Pre-specified
    Analysis type
    other [66]
    P-value
    < 0.0001 [67]
    Method
    ANOVA
    Confidence interval
    Notes
    [66] - Rituximab (1.0 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.
    [67] - Secondary endpoint in hierarchical testing structure.

    Secondary: Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104

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    End point title
    Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104
    End point description
    The SF-36 is a 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 (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. Means are adjusted for baseline value, Rheumatoid Factor status and region.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52, Week 104
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    240 [68]
    236 [69]
    242 [70]
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 52 (n=239,236,241)
    8.953 ± 9.3986
    11.022 ± 9.6246
    12.205 ± 9.4986
        Week 104 (n=240,236,242)
    8.617 ± 9.85
    11.032 ± 9.9631
    12.649 ± 10.4331
    Notes
    [68] - ITT population
    [69] - ITT population
    [70] - ITT population
    No statistical analyses for this end point

    Secondary: Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104

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    End point title
    Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104
    End point description
    The SF-36 is a 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 (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. Means are adjusted for baseline value, Rheumatoid Factor status and region.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52, Week 104
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    240 [71]
    236 [72]
    242 [73]
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 52 (n=239,236,241)
    6.689 ± 13.116
    7.718 ± 11.8903
    8.167 ± 12.1709
        Week 104 (n= 240,236,242)
    6.295 ± 13.9813
    7.617 ± 12.0793
    9.066 ± 12.5325
    Notes
    [71] - ITT population
    [72] - ITT population
    [73] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52

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    End point title
    Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52
    End point description
    The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Each domain has at least two component questions. There are four possible responses for each component on a scale of 0 (without difficulty) to 3 (unable to do). Higher scores = greater dysfunction. Improved:HAQ-DI score change ≤-0.22 Unchanged:HAQ-DI score change -0.22 to 0.22 Worsened:HAQ score ≥0.22
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    249 [74]
    249 [75]
    250 [76]
    Units: Percentage of participants
    number (not applicable)
        Improved
    77.1
    86.7
    86.8
        Unchanged
    14.1
    8.8
    8
        Worsened
    8.4
    3.6
    4.4
        Not Assessable
    0.4
    0.8
    0.8
    Notes
    [74] - ITT population
    [75] - ITT population
    [76] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Minimally Clinically Important Difference (MCID) in the SF-36 Physical Health Component Score at Week 52

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    End point title
    Percentage of Participants With Minimally Clinically Important Difference (MCID) in the SF-36 Physical Health Component Score at Week 52
    End point description
    MCID is defined as a change from baseline in SF-36 Physical Health Component Score of >5.42. SF-36 is a 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 (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    239 [77]
    236 [78]
    242 [79]
    Units: percentage of participants
        number (not applicable)
    63.2
    69.9
    76.4
    Notes
    [77] - ITT population
    [78] - ITT population
    [79] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Minimally Clinically Important Difference (MCID) in the Short-Form 36 ( SF-36) Mental Health Component Score at Week 52

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    End point title
    Percentage of Participants With Minimally Clinically Important Difference (MCID) in the Short-Form 36 ( SF-36) Mental Health Component Score at Week 52
    End point description
    MCID is defined as a change from baseline in SF-36 Mental Health Component Score of >6.33. SF-36 is a 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 (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    239 [80]
    236 [81]
    242 [82]
    Units: Percentage of participants
        number (not applicable)
    49
    50.8
    57
    Notes
    [80] - ITT population
    [81] - ITT population
    [82] - ITT population
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Modified Total Sharp Score at Week 104

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    End point title
    Change From Baseline in the Modified Total Sharp Score at Week 104
    End point description
    The modified Total Sharp Score is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    229
    238
    243
    Units: Score on a scale
        arithmetic mean (standard deviation)
    1.948 ± 5.5782
    0.761 ± 2.6181
    0.406 ± 1.4312
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 104: Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline rheumatoid factor (RF) status
    Comparison groups
    Rituximab (0.5 g X 2) + Methotrexate v Placebo Plus (+) Methotrexate
    Number of subjects included in analysis
    467
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [83]
    Method
    Van-Elteren
    Confidence interval
    Notes
    [83] - This was a secondary endpoint in a hierarchical testing structure.

    Secondary: Change From Baseline in the Total Erosion Score at Week 104

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    End point title
    Change From Baseline in the Total Erosion Score at Week 104
    End point description
    Total Erosion Score is determined by evaluation of 14 sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces). The change from the score at baseline to Week 104 is calculated.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    229 [84]
    238 [85]
    243 [86]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    1.315 ± 3.2466
    0.499 ± 1.7221
    0.227 ± 0.7939
    Notes
    [84] - MITT population
    [85] - MITT population
    [86] - MITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants Without Radiographic Progression at Week 104

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    End point title
    Percentage of Participants Without Radiographic Progression at Week 104
    End point description
    Percentage of participants without radiographic progression at Week 104, defined as change in total modified Sharp Score (TMSS) ≤0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    233 [87]
    239 [88]
    244 [89]
    Units: Percentage of participants
        number (not applicable)
    37.3
    49.4
    56.6
    Notes
    [87] - MITT population
    [88] - MITT population
    [89] - MITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants Without Radiographic Progression in the Total Erosion Score at Week 104

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    End point title
    Percentage of Participants Without Radiographic Progression in the Total Erosion Score at Week 104
    End point description
    Total Erosion Score is determined by evaluation of fourteen sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces). The score at baseline is compared to the score at Week 104. No progression is defined as a change from score at screening to Week 104 ≤0.
    End point type
    Secondary
    End point timeframe
    Week 104
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    233 [90]
    239 [91]
    244 [92]
    Units: Percentage of participants
        number (not applicable)
    38.2
    52.7
    58.6
    Notes
    [90] - MITT population
    [91] - MITT population
    [92] - MITT population
    No statistical analyses for this end point

    Secondary: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 104

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    End point title
    Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 104
    End point description
    The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a participant completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0 (without any difficulty) to 4 (unable to do). HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Plus (+) Methotrexate Rituximab (0.5 g X 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
    Number of subjects analysed
    248 [93]
    247 [94]
    248 [95]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.806 ± 0.7968
    -1038 ± 0.8142
    -1.055 ± 0.7901
    Notes
    [93] - ITT population
    [94] - ITT population
    [95] - ITT population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Rituximab (0.5 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.
    Comparison groups
    Rituximab (0.5 g X 2) + Methotrexate v Placebo Plus (+) Methotrexate
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    other [96]
    P-value
    < 0.0001
    Method
    ANOVA
    Confidence interval
    Notes
    [96] - Secondary endpoint in hierarchical testing structure.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Rituximab (1.0 g x 2) + Methotrexate versus Placeb
    Comparison groups
    Rituximab (1.0 g x 2) + Methotrexate v Placebo Plus (+) Methotrexate
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [97]
    Method
    ANOVA
    Confidence interval
    Notes
    [97] - Secondary endpoint in hierarchical testing structure.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline to End of ESFU, a total of 96 weeks after the end of 3 year Treatment Period.
    Adverse event reporting additional description
    Safety Population includes all participants who received at least one dose of study drug, grouped as treated. After Week 104 participants in the placebo group were eligible to receive either Rituximab 2 X 0.5 g + MTX or Rituximab 2 X 1.0g + MTX. Adverse events reported for placebo patients after switching to Rituximab are not included below.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo + Methotrexate
    Reporting group description
    Treatment period : Placebo intravenously on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. From Week 104 participants were eligible to receive Rituximab 2 X 0.5 g or Rituximab 2 X 1.0 g every 24 weeks. At the end of 3 year treatment period participants were followed for a 48-Week Safety Follow-Up. During the SFU period no further study drug was administered. At the end of 48-Week SFU participants entered ESFU. Participants who did not receive any study drug were not required to enter ESFU for a period of additional 48 weeks. During the ESFU period no further study drug was administered.

    Reporting group title
    Rituximab (1.0 g x 2) + Methotrexate
    Reporting group description
    Treatment period: Rituximab intravenously at a dose of 1.0 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS-ESR) result was ≥2.6. At the end of 3 year treatment period participants were followed for a 48-Week Safety Follow-Up. During the SFU period no further study drug was administered. At the end of 48-Week SFU participants entered ESFU. Only participants who received the study drug entered ESFU for a period of additional 48 weeks. During the ESFU period no further study drug was administered.

    Reporting group title
    Rituximab (0.5 g x 2) + Methotrexate
    Reporting group description
    Treatment period: Rituximab intravenously at a dose of 0.5 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS-ESR) result was ≥2.6. At the end of 3 year treatment period participants were followed for a 48-Week Safety Follow-Up. During the SFU period no further study drug was administered. At the end of 48-Week SFU participants entered ESFU. Only participants who received the study drug entered ESFU for a period of additional 48 weeks. During the ESFU period no further study drug was administered.

    Serious adverse events
    Placebo + Methotrexate Rituximab (1.0 g x 2) + Methotrexate Rituximab (0.5 g x 2) + Methotrexate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 249 (19.28%)
    58 / 263 (22.05%)
    54 / 348 (15.52%)
         number of deaths (all causes)
    4
    2
    4
         number of deaths resulting from adverse events
    Vascular disorders
    Venous insufficiency
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angiopathy
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaplastic large-cell lymphoma
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic Neoplasm
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Monoclonal gammopathy
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paget's disease of nipple
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Primary mediastinal large B-cell lymphoma
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer stage II
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 263 (0.76%)
    2 / 348 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical failure
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulcer haemorrhage
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 263 (0.76%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug dependence
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 249 (1.20%)
    1 / 263 (0.38%)
    2 / 348 (0.57%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Accident
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 263 (0.76%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    2 / 348 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve sclerosis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 263 (0.76%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal hypertrophy
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status asthmaticus
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid arteriosclerosis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia obstructive
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis Ulcerative
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal dysplasia
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    2 / 348 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic ulcer
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 263 (0.76%)
    3 / 348 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 249 (2.41%)
    4 / 263 (1.52%)
    7 / 348 (2.01%)
         occurrences causally related to treatment / all
    4 / 6
    2 / 4
    1 / 7
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    4 / 249 (1.61%)
    0 / 263 (0.00%)
    2 / 348 (0.57%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 249 (0.00%)
    3 / 263 (1.14%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    2 / 348 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    2 / 348 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute tonsillitis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 249 (0.00%)
    0 / 263 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 263 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 263 (0.38%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo + Methotrexate Rituximab (1.0 g x 2) + Methotrexate Rituximab (0.5 g x 2) + Methotrexate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    193 / 249 (77.51%)
    208 / 263 (79.09%)
    232 / 348 (66.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 249 (7.23%)
    24 / 263 (9.13%)
    22 / 348 (6.32%)
         occurrences all number
    20
    25
    27
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    53 / 249 (21.29%)
    67 / 263 (25.48%)
    69 / 348 (19.83%)
         occurrences all number
    100
    121
    150
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 249 (4.42%)
    24 / 263 (9.13%)
    19 / 348 (5.46%)
         occurrences all number
    13
    27
    24
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    25 / 249 (10.04%)
    19 / 263 (7.22%)
    14 / 348 (4.02%)
         occurrences all number
    25
    23
    15
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 249 (7.23%)
    31 / 263 (11.79%)
    17 / 348 (4.89%)
         occurrences all number
    23
    40
    19
    Dizziness
         subjects affected / exposed
    13 / 249 (5.22%)
    20 / 263 (7.60%)
    12 / 348 (3.45%)
         occurrences all number
    15
    21
    14
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    42 / 249 (16.87%)
    46 / 263 (17.49%)
    45 / 348 (12.93%)
         occurrences all number
    51
    60
    54
    Diarrhoea
         subjects affected / exposed
    15 / 249 (6.02%)
    18 / 263 (6.84%)
    24 / 348 (6.90%)
         occurrences all number
    23
    29
    25
    Dyspepsia
         subjects affected / exposed
    13 / 249 (5.22%)
    14 / 263 (5.32%)
    15 / 348 (4.31%)
         occurrences all number
    14
    14
    16
    Gastritis
         subjects affected / exposed
    13 / 249 (5.22%)
    10 / 263 (3.80%)
    11 / 348 (3.16%)
         occurrences all number
    13
    13
    12
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    35 / 249 (14.06%)
    38 / 263 (14.45%)
    37 / 348 (10.63%)
         occurrences all number
    47
    51
    50
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    42 / 249 (16.87%)
    29 / 263 (11.03%)
    30 / 348 (8.62%)
         occurrences all number
    69
    47
    45
    Back pain
         subjects affected / exposed
    14 / 249 (5.62%)
    9 / 263 (3.42%)
    19 / 348 (5.46%)
         occurrences all number
    16
    11
    20
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    44 / 249 (17.67%)
    58 / 263 (22.05%)
    59 / 348 (16.95%)
         occurrences all number
    70
    126
    103
    Nasopharyngitis
         subjects affected / exposed
    43 / 249 (17.27%)
    52 / 263 (19.77%)
    53 / 348 (15.23%)
         occurrences all number
    71
    76
    81
    Urinary tract infection
         subjects affected / exposed
    26 / 249 (10.44%)
    43 / 263 (16.35%)
    36 / 348 (10.34%)
         occurrences all number
    40
    76
    51
    Bronchitis
         subjects affected / exposed
    15 / 249 (6.02%)
    20 / 263 (7.60%)
    32 / 348 (9.20%)
         occurrences all number
    23
    35
    39
    Sinusitis
         subjects affected / exposed
    11 / 249 (4.42%)
    20 / 263 (7.60%)
    23 / 348 (6.61%)
         occurrences all number
    18
    28
    30
    Pharyngitis
         subjects affected / exposed
    16 / 249 (6.43%)
    14 / 263 (5.32%)
    14 / 348 (4.02%)
         occurrences all number
    22
    20
    22
    Influenza
         subjects affected / exposed
    11 / 249 (4.42%)
    16 / 263 (6.08%)
    9 / 348 (2.59%)
         occurrences all number
    15
    19
    13
    Gastroenteritis
         subjects affected / exposed
    7 / 249 (2.81%)
    16 / 263 (6.08%)
    9 / 348 (2.59%)
         occurrences all number
    8
    17
    10

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2006
    Safety information was updated and eligibility criteria and other study procedures were clarified.
    09 Mar 2007
    Enrollment criteria was updated in line with protocol to allow patients who are Hepatitis B core antibody (HbcAb) positive / DNA negative to be enrolled; Safety information (infections including reports of progressive multifocal leukoencephalopathy, PML) was updated. Eligibility criteria and other study procedures were clarified.
    24 Jul 2007
    Sample size and safety information were updated. Study procedures were clarified.
    06 Mar 2009
    Placebo switch dose was amended and safety information updated. Extension of study was specified. Safety information (including PML Update) was updated and study procedures were clarified.
    26 Nov 2009
    This Amendment was to implement dosing discontinuation due to progressive multifocal leukoencephalopathy (PML) reports in Rheumatoid Arthritis (RA) patients. All patients exposed to MabThera (Rituximab) went into safety follow up SFU.
    06 Sep 2012
    This amendment was for termination of extended B cell Safety Follow-UP (SFU).

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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