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    Clinical Trial Results:
    A Randomized, Placebo Controlled, Double-blind, Parallel Group, International Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate, Compared to Methotrexate Monotherapy, in Patients With Active Rheumatoid Arthritis

    Summary
    EudraCT number
    2005-002392-32
    Trial protocol
    IE   GB   SE   DE   SI  
    Global end of trial date
    24 Jul 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Oct 2016
    First version publication date
    19 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WA17045
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00299130
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Genentech Protocol Identification: U2973g (SERENE)
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Sep 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To determine the efficacy and safety at Week 24 of rituximab 500 milligrams (mg) intravenous ( IV) times (x) 2 and rituximab 1000 mg IV x 2 when used in combination with methotrexate (MTX) compared to continued MTX monotherapy in participants with active rheumatoid arthritis (RA) that currently have an inadequate clinical response to MTX. 2. To investigate by a population analysis approach the pharmacokinetics (PK) of rituximab in the target RA participant population and the influence of covariates on the PK parameters. 3. To explore a dose separation of rituximab 500 mg IV ×2 from rituximab 1000 mg IV ×2. 4. To explore the long-term efficacy and safety of further courses of rituximab.
    Protection of trial subjects
    This study was conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study fully adhered to the principles outlined in “Guideline for Good Clinical Practice” International Conference on Harmonization (ICH) Tripartite Guideline (January 1997) or with local law if it afforded greater protection to the individual. The investigator additionally ensured that the basic principles of “Good Clinical Practice” as outlined in the current version of the Federal Regulations (CFR) Title 21, subchapter D, part 312, “Responsibilities of Sponsors and Investigators”, part 50, “Protection of Human Patients”, and part 56, “Institutional Review Boards”, were adhered to. In other countries where “Guideline for Good Clinical Practice” exist, the sponsor and the investigators strictly ensured adherence to the stated provisions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Oct 2005
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    48 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovenia: 23
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    United Kingdom: 40
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Poland: 56
    Country: Number of subjects enrolled
    Guatemala: 13
    Country: Number of subjects enrolled
    Mexico: 69
    Country: Number of subjects enrolled
    Romania: 35
    Country: Number of subjects enrolled
    United States: 237
    Country: Number of subjects enrolled
    Canada: 16
    Worldwide total number of subjects
    511
    EEA total number of subjects
    176
    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)
    434
    From 65 to 84 years
    77
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 511 participants were recruited and randomized between 27 Oct 2005 and 15 Nov 2006. Of these, 2 participants were randomized but received no infusions (one violated inclusion criteria and the other was randomized to rituximab 2 x 1.0 gram [g] + methotrexate [MTX] but failed to return). A total of 509 participants were treated.

    Pre-assignment
    Screening details
    Of the 509 participants, one participant was randomized first to rituximab 2 x 1.0 g + MTX and then to rituximab 2 x 0.5 g + MTX. No assessments were recorded or medication given after first randomization and all data used in analyses was following the second randomization; hence, participant is included only in rituximab 2 x 0.5 g + MTX arm.

    Period 1
    Period 1 title
    Treatment Period (up to 5 Years)
    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 + MTX
    Arm description
    Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 milligrams (mg) intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo to rituximab intravenous infusion.

    Arm title
    Rituximab 2 x 0.5 g + MTX
    Arm description
    Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Ro 45-2294
    Other name
    MabThera, Rituxan
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion.

    Arm title
    Rituximab 2 x 1.0 g + MTX
    Arm description
    Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Ro 45-2294
    Other name
    MabThera, Rituxan
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion.

    Number of subjects in period 1
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Started
    172
    168
    171
    Treated
    172
    167
    170
    Completed 24 Weeks
    159
    162
    166
    Completed 48 Weeks
    155
    157
    158
    Completed 144 Weeks
    133
    138
    132
    Completed
    119
    125
    121
    Not completed
    53
    43
    50
         Death
    1
    3
    1
         Insufficient Therapeutic Response
    19
    6
    6
         Reason Not Specified
    4
    6
    4
         Refused Treatment
    12
    12
    19
         Protocol Violation
    -
    1
    -
         Failure to Return
    4
    6
    6
         Consent withdrawn by subject
    -
    1
    1
         Adverse Event
    13
    8
    13
    Period 2
    Period 2 title
    Safety Follow-up (SFU) (48 Weeks)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo + MTX
    Arm description
    Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 milligrams (mg) intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo to rituximab intravenous infusion.

    Arm title
    Rituximab 2 x 0.5 g + MTX
    Arm description
    Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Ro 45-2294
    Other name
    MabThera, Rituxan
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion.

    Arm title
    Rituximab 2 x 1.0 g + MTX
    Arm description
    Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Ro 45-2294
    Other name
    MabThera, Rituxan
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion.

    Number of subjects in period 2
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Started
    119
    125
    121
    Completed
    122
    120
    123
    Not completed
    45
    45
    45
         No SFU Week 48 Date Recorded
    -
    1
    -
         Death
    4
    5
    3
         Withdrawal by Subject
    22
    22
    21
         Failure to Return
    14
    7
    15
         Administrative/Other
    4
    9
    4
         Did not Co-operate
    1
    1
    2
    Joined
    48
    40
    47
         Discontinued Treatment, Entered SFU
    48
    40
    47
    Period 3
    Period 3 title
    Extended SFU (ESFU) (up to 5.1 Years)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Rituximab 2 x 0.5 g + MTX
    Arm description
    Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Ro 45-2294
    Other name
    MabThera, Rituxan
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion.

    Arm title
    Rituximab 2 x 1.0 g + MTX
    Arm description
    Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Ro 45-2294
    Other name
    MabThera, Rituxan
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion.

    Number of subjects in period 3 [1]
    Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Started
    82
    44
    Completed
    74
    38
    Not completed
    8
    6
         Death
    3
    -
         'Did not Co-operate/Withdrew Consent '
    3
    4
         Failure to Return
    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 whose peripheral CD20+ B cells remained depleted (less than the laboratory lower limit of normal) after the week 48 SFU visit, participated in the ESFU period, with the safety assessments described for SFU week 48 being performed at 12 week intervals until peripheral B cells returned to within normal ranges or baseline levels, whichever was lower.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + MTX
    Reporting group description
    Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 milligrams (mg) intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Reporting group title
    Rituximab 2 x 0.5 g + MTX
    Reporting group description
    Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Reporting group title
    Rituximab 2 x 1.0 g + MTX
    Reporting group description
    Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Reporting group values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX Total
    Number of subjects
    172 168 171 511
    Age categorical
    Units: Subjects
    Age continuous
    Age data was reported for safety population (N = 509).
    Units: years
        arithmetic mean (standard deviation)
    52.16 ± 12.39 51.91 ± 12.93 51.3 ± 12.64 -
    Gender categorical
    Units: Subjects
        Male
    25 34 32 91
        Female
    147 133 138 418
        Not Available
    0 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Placebo + MTX
    Reporting group description
    Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 milligrams (mg) intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Reporting group title
    Rituximab 2 x 0.5 g + MTX
    Reporting group description
    Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Reporting group title
    Rituximab 2 x 1.0 g + MTX
    Reporting group description
    Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
    Reporting group title
    Placebo + MTX
    Reporting group description
    Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 milligrams (mg) intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Reporting group title
    Rituximab 2 x 0.5 g + MTX
    Reporting group description
    Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Reporting group title
    Rituximab 2 x 1.0 g + MTX
    Reporting group description
    Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
    Reporting group title
    Rituximab 2 x 0.5 g + MTX
    Reporting group description
    Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Reporting group title
    Rituximab 2 x 1.0 g + MTX
    Reporting group description
    Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Subject analysis set title
    Rituximab + MTX
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received 0.5 g or 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Primary: Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24

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    End point title
    Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24
    End point description
    Achieving ACR20 required a ≥20 percent (%) improvement compared with Baseline in tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), and a 20% improvement in three of the following five additional measurements: •Physician's global assessment of disease activity (assessed using a 100 millimeter (mm) Visual Analog Scale [VAS]) •Participant's global assessment of disease activity (assessed using a 100 mm VAS) •Participant's assessment of pain (assessed using a 100 mm VAS) •Health Assessment Questionnaire (HAQ; a participant-completed questionnaire consisting of 20 questions, scored from 0-3) •Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR) Participants who withdrew prematurely from the study prior to week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders. ITT Population
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 Each component calculated using the last observation carried forward (LOCF).
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    167
    170
    Units: Percentage of Participants
        number (not applicable)
    23.3
    54.5
    50.6
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo + MTX v Rituximab 2 x 0.5 g + MTX
    Number of subjects included in analysis
    339
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    0.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.21
         upper limit
    0.41
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo + MTX v Rituximab 2 x 1.0 g + MTX
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted Difference
    Point estimate
    0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.17
         upper limit
    0.37

    Secondary: Percentage of Participants With an ACR50 Response at Week 24

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    End point title
    Percentage of Participants With an ACR50 Response at Week 24
    End point description
    Achieving ACR50 required at least a 50% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 50% improvement in three of the following five additional measurements: •Physician's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's assessment of pain (assessed using a 100 mm VAS); •HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3; •Acute phase reactant: CRP or, if CRP was missing, ESR. Participants who withdrew prematurely from the study prior to week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    167
    170
    Units: Percentage of Participants
        number (not applicable)
    9.3
    26.3
    25.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants With an ACR70 Response at Week 24

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    End point title
    Percentage of Participants With an ACR70 Response at Week 24
    End point description
    To achieve an ACR70 required at least a 70% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 70% improvement in three of the following five additional measurements: •Physician's global assessment of disease activity (assessed using a 100 mm VAS); •Participant's global assessment of disease activity (assessed using a 100 mm VAS); •Participant's assessment of pain (assessed using a 100 mm VAS); •HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3; •Acute phase reactant: CRP or, if CRP was missing, ESR. Participants who withdrew prematurely from the study prior to week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    167
    170
    Units: Percentage of Participants
        number (not applicable)
    5.2
    9
    10
    No statistical analyses for this end point

    Secondary: Change From Baseline in Disease Activity Score (DAS28-ESR) at Week 24

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    End point title
    Change From Baseline in Disease Activity Score (DAS28-ESR) at Week 24
    End point description
    The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: •The number of swollen and tender joints assessed using the 28-joint count; •ESR; •Participant's global assessment of disease activity measured on a 100 mm visual analog scale. The DAS28 score ranges from zero to ten. A DAS28 score above 5.1 means high disease activity whereas a DAS28 less than or equal to 3.2 indicates low disease activity. Remission is achieved by a DAS28 lower than 2.6. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    171
    166
    168
    Units: DAS28-ESR
        arithmetic mean (standard deviation)
    -0.76 ± 1.304
    -1.71 ± 1.334
    -1.68 ± 1.342
    No statistical analyses for this end point

    Secondary: Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 24

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    End point title
    Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 24
    End point description
    A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS28 score. The DAS28 score ranges from 0-10, with higher scores indicating more disease activity. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score of less than or equal to (≤)3.2. A Moderate Response is defined as either: •an improvement (decrease) in the DAS28 of greater than (>)0.6 and ≤1.2 from Baseline and attainment of a DAS28 score of ≤5.1 or, •an improvement (decrease) in the DAS28 of >1.2 from Baseline and attainment of a DAS28 score of >3.2. No Response is defined as either an improvement (decrease) in the DAS28 of ≤0.6, or an improvement (decrease) in the DAS28 of >0.6 and ≤1.2 and attainment of a DAS28 of >5.1. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    167
    170
    Units: Percentage of Participants
    number (not applicable)
        No Response
    66.3
    33.5
    37.1
        Moderate Response
    29.1
    49.1
    51.2
        Good Response
    4.7
    17.4
    11.8
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Swollen Joint Count at Week 24 and Week 48

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    End point title
    Percent Change From Baseline in Swollen Joint Count at Week 24 and Week 48
    End point description
    Sixty-six joints were assessed and classified as swollen/not swollen by pressure and joint manipulation on physical examination. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value] times (*)100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    166
    170
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 24 [n=172, 166, 170]
    -21.6 ± 65.82
    -47.4 ± 43.49
    -49.1 ± 38.59
        Week 48 [n=172, 166, 170]
    -38.9 ± 66.83
    -54 ± 38.66
    -59.3 ± 37.04
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Tender Joint Count at Week 24 and Week 48

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    End point title
    Percent Change From Baseline in Tender Joint Count at Week 24 and Week 48
    End point description
    Sixty-eight joints were assessed and classified as tender/not tender by pressure and joint manipulation on physical examination. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    166
    170
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 24 [n=172, 166, 170]
    -14.2 ± 69.2
    -42.5 ± 64.41
    -31.5 ± 66.52
        Week 48 [n=172, 166, 170]
    -37.1 ± 55.08
    -50.2 ± 62.74
    -45.1 ± 62.64
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Participant's Global Assessment of Disease Activity

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    End point title
    Percent Change From Baseline in Participant's Global Assessment of Disease Activity
    End point description
    The participant's overall assessment of their current disease activity measured on a 100 mm horizontal VAS. The left-hand extreme of the line (0 mm) was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme (100 mm) as "maximum disease activity" (maximum arthritis disease activity). The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    171
    166
    169
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 24 [n=171, 166, 169]
    -14 ± 48.94
    -31.5 ± 46.4
    -29.1 ± 54.43
        Week 48 [n=171, 166, 169]
    -28 ± 50.78
    -39.7 ± 40.53
    -36.6 ± 47.6
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Participant’s Pain Assessment

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    End point title
    Percent Change From Baseline in Participant’s Pain Assessment
    End point description
    The participant’s assessment of their current level of pain on a 100 mm horizontal VAS, where the left-hand extreme of the line (0 mm) was described as "no pain" and the right-hand extreme (100 mm) as "unbearable pain". The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    171
    166
    169
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 24 [n=171, 166, 169]
    -9.7 ± 52.58
    -25.7 ± 58.52
    -29.1 ± 53.11
        Week 48 [n=171, 166, 169]
    -24.4 ± 60.22
    -35.5 ± 50.45
    -36.3 ± 47.87
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Physician’s Global Assessment of Disease Activity

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    End point title
    Percent Change From Baseline in Physician’s Global Assessment of Disease Activity
    End point description
    The physician’s assessment of the participant's current disease activity on a 100 mm horizontal VAS, where the left-hand extreme of the line (0 mm) was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme (100 mm) as "maximum disease activity". The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    166
    170
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 24 [n=172, 166, 170]
    -25.3 ± 38.52
    -36.9 ± 61.26
    -35.4 ± 46.99
        Week 48 [n=172, 166, 170]
    -39.4 ± 39.95
    -40.5 ± 74.54
    -49 ± 40.01
    No statistical analyses for this end point

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

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    End point title
    Percent Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score
    End point description
    The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    165
    170
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 24 [n=172, 165, 170]
    -14.7 ± 38.41
    -26.9 ± 40.89
    -23.4 ± 49.52
        Week 48 [n=172, 165, 170]
    -22.6 ± 39.63
    -30.2 ± 41.64
    -30.6 ± 39.95
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in C-Reactive Protein

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    End point title
    Percent Change From Baseline in C-Reactive Protein
    End point description
    CRP was measured from blood samples by a central laboratory as a marker for inflammation. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    166
    170
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 24 [n=172, 166, 170]
    58.1 ± 385.23
    -27.5 ± 84.36
    -23.1 ± 119.75
        Week 48 [n=172, 166, 170]
    40.1 ± 402.67
    -37.3 ± 94.65
    -34.9 ± 82.4
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Erythrocyte Sedimentation Rate

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    End point title
    Percent Change From Baseline in Erythrocyte Sedimentation Rate
    End point description
    ESR indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    166
    169
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 24 [n=172, 166, 169]
    8 ± 130.71
    -28 ± 42.2
    -29.2 ± 52.32
        Week 48 [n=172, 166, 169]
    -14.5 ± 68.55
    -31.3 ± 49.72
    -36.7 ± 51.49
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Short Form 36 Health Survey (SF-36) Summary Scores (Physical and Mental Components)

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    End point title
    Percent Change From Baseline in Short Form 36 Health Survey (SF-36) Summary Scores (Physical and Mental Components)
    End point description
    SF-36 measured impact of disease on overall quality of life and consists of 36 questions split into 2 major components: physical health and mental health. Physical health includes four domains: physical health, bodily pain, physical functioning and physical role limitations. Under the mental health domain there are four domains; mental health, vitality, social functioning, and emotional role limitation. Individual domain scores are aggregated to derive a physical-component summary score and a mental-component summary score which range from 0 to 100, with higher scores indicating a better level of functioning. Percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A positive percentage change from baseline score indicates an improvement. For each parameter/ treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    154
    154
    162
    Units: Percent Change
    arithmetic mean (standard deviation)
        Physical Component: Week 24 [n=147, 152, 155]
    11.1 ± 27.63
    23.7 ± 31.63
    22.8 ± 33.09
        Physical Component: Week 48 [n=154, 154, 162]
    21.3 ± 30.99
    26.4 ± 35.81
    27.4 ± 31.93
        Mental Component: Week 24 [n=147, 152, 155]
    8.4 ± 29.43
    12.6 ± 29.13
    19.6 ± 56.64
        Mental Component: Week 48 [n=154, 154, 162]
    12.7 ± 30.52
    18.4 ± 38.87
    18.7 ± 57.34
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) General Health Domain Score

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    End point title
    Change From Baseline in Short Form 36 Health Survey (SF-36) General Health Domain Score
    End point description
    The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    138
    154
    155
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 24 [n=138, 154, 155]
    2.078 ± 7.3032
    3.532 ± 8.2747
    3.866 ± 9.2154
        Week 48 [n=137, 148, 147]
    4.214 ± 8.2352
    4.165 ± 9.5894
    4.362 ± 8.1242
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Bodily Pain Domain Score

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    End point title
    Change From Baseline in Short Form 36 Health Survey (SF-36) Bodily Pain Domain Score
    End point description
    The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    138
    152
    156
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 24 [n=138, 152, 156]
    3.304 ± 8.5631
    6.931 ± 8.2254
    7.604 ± 8.5238
        Week 48 [n=137, 147, 147]
    8.449 ± 9.3543
    8.079 ± 9.5435
    8.964 ± 8.989
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Functioning Domain Score

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    End point title
    Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Functioning Domain Score
    End point description
    The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    138
    154
    154
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 24 [n=138, 154, 154]
    3.553 ± 8.4181
    5.46 ± 8.3099
    5.653 ± 9.6817
        Week 48 [n=137, 148, 146]
    6.212 ± 9.6882
    6.778 ± 8.7117
    6.854 ± 9.3833
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Role Limitations Domain Score

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    End point title
    Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Role Limitations Domain Score
    End point description
    The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    137
    153
    156
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 24 [n=136, 153, 156]
    2.713 ± 8.7263
    5.618 ± 9.0459
    5.175 ± 8.8018
        Week 48 [n=137, 148, 147]
    6.423 ± 9.6752
    6.812 ± 9.8633
    6.497 ± 8.482
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Health Domain Score

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    End point title
    Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Health Domain Score
    End point description
    The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    137
    153
    156
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 24 [n=137, 153, 156]
    3.278 ± 8.685
    2.77 ± 9.9943
    4.486 ± 9.493
        Week 48 [n=135, 147, 147]
    3.89 ± 8.7493
    4.583 ± 10.5625
    4.224 ± 9.9831
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Vitality Domain Score

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    End point title
    Change From Baseline in Short Form 36 Health Survey (SF-36) Vitality Domain Score
    End point description
    The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    137
    154
    156
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 24 [n=137, 154, 156]
    3.631 ± 8.7662
    4.23 ± 9.3631
    5.91 ± 9.5802
        Week 48 [n=135, 147, 147]
    6.853 ± 9.8221
    5.925 ± 10.1495
    5.869 ± 9.6168
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Social Functioning Domain Score

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    End point title
    Change From Baseline in Short Form 36 Health Survey (SF-36) Social Functioning Domain Score
    End point description
    The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    138
    154
    156
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 24 [n=138, 154, 156]
    2.529 ± 9.6435
    5.985 ± 10.2986
    6.468 ± 10.8868
        Week 48 [n=137, 148, 147]
    6.569 ± 10.6674
    7.112 ± 11.5329
    6.159 ± 11.0244
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Emotional Role Limitations Domain Score

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    End point title
    Change From Baseline in Short Form 36 Health Survey (SF-36) Emotional Role Limitations Domain Score
    End point description
    The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    137
    151
    155
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 24 [n=136, 151, 155]
    1.829 ± 11.5405
    4.634 ± 11.6419
    4.464 ± 13.6883
        Week 48 [n=137, 146, 146]
    4.724 ± 12.2649
    6.257 ± 12.964
    4.446 ± 13.4036
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Scores

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    End point title
    Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Scores
    End point description
    The FACIT questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants respond to the questions using a value in the range of 0 (not at all) to 4 (very much). The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT subscale score ranges from 0 to 52, where higher scores represent less fatigue. A positive change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    170
    165
    169
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 24 [n=170, 165, 168]
    2.661 ± 9.5093
    5.564 ± 9.7438
    6.398 ± 10.2143
        Week 48 [170, 165, 169]
    5.506 ± 10.9651
    6.269 ± 9.7495
    6.203 ± 9.7833
    No statistical analyses for this end point

    Secondary: Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 24

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    End point title
    Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 24
    End point description
    The DAS28 is a composite score to measure disease activity in participants with rheumatoid arthritis, derived from the following variables: •The number of swollen and tender joints assessed using the 28-joint count; •ESR; •Patient's global assessment of disease activity measured on a 100 mm VAS. The DAS28 score ranges from zero to ten. DAS28 above 5.1 indicates high disease activity. Low disease activity is defined by a DAS28 score less than or equal to 3.2. Remission is defined by a DAS28 score less than 2.6. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 24 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    166
    170
    Units: Percentage of Participants
    number (not applicable)
        Low Disease Activity
    4.7
    17.5
    12.4
        Clinical Remission
    2.3
    9.6
    9.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 24

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    End point title
    Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 24
    End point description
    The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from baseline score indicates an improvement. Improved HAQ-DI is defined as a change from Baseline score ≤-0.22. An Unchanged HAQ-DI is defined as a change from Baseline score >-0.22 and <0.22. A worsened HAQ-DI score is defined as a change from Baseline score of ≥0.22. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    165
    170
    Units: Percentage of Participants
    number (not applicable)
        Improved
    47.7
    66.1
    58.2
        No Change
    32.6
    23.6
    32.4
        Worsened
    19.8
    10.3
    9.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 48

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    End point title
    Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 48
    End point description
    The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from baseline score indicates an improvement. Improved HAQ-DI is defined as a change from Baseline score ≤-0.22. An Unchanged HAQ-DI is defined as a change from Baseline score >-0.22 and <0.22. A worsened HAQ-DI score is defined as a change from Baseline score of ≥0.22. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    165
    170
    Units: Percentage of Participants
    number (not applicable)
        Improved
    54.7
    73.3
    68.8
        No Change
    29.1
    17
    25.3
        Worsened
    16.3
    9.7
    5.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 48

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    End point title
    Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 48
    End point description
    A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of >1.2 compared with Baseline and attainment of a DAS28 score ≤3.2. A Moderate Response is defined as either: •an improvement (decrease) in the DAS28 >0.6 and ≤1.2 and attainment of a DAS28 score of ≤5.1 or, •an improvement (decrease) in the DAS28 of >1.2 and attainment of a DAS28 score of >3.2. No Response is defined as either an improvement (decrease) in the DAS28 of ≤0.6, or an improvement (decrease) in the DAS28 of >0.6 and ≤1.2 and attainment of a DAS28 score of 5.1 or higher. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    167
    170
    Units: Percentage of Participants
    number (not applicable)
        No Response
    41.3
    26.9
    31.8
        Moderate Response
    41.9
    53.3
    47.6
        Good Response
    16.9
    19.8
    20.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 48

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    End point title
    Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 48
    End point description
    The DAS28 is a composite score to measure disease activity in participants with rheumatoid arthritis, derived from the following variables: •The number of swollen and tender joints assessed using the 28-joint count; •ESR; •Patient's global assessment of disease activity measured on a 100 mm VAS. The DAS28 score ranges from zero to ten. DAS28 above 5.1 indicates high disease activity. Low disease activity is defined by a DAS28 score ≤3.2. Remission is defined by a DAS28 score <2.6. ITT Population: included participants with available data.
    End point type
    Secondary
    End point timeframe
    Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    171
    165
    169
    Units: Percentage of Participants
    number (not applicable)
        Low Disease Activity
    18.1
    20
    24.3
        Clinical Remission
    7
    9.1
    11.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants With an ACR50 Response at Week 48

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    End point title
    Percentage of Participants With an ACR50 Response at Week 48
    End point description
    To achieve an ACR50 required at least a 50% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 50% improvement in three of the following five additional measurements: •Physician's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's assessment of pain (assessed using a 100 mm VAS); •HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3; •Acute phase reactant: CRP or, if CRP was missing, ESR. Participants who withdrew prematurely from the study prior to week 48, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48 Each component calculated using the LOCF.
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    167
    170
    Units: Percentage of Participants
        number (not applicable)
    18.6
    32.9
    34.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With an ACR70 Response at Week 48

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    End point title
    Percentage of Participants With an ACR70 Response at Week 48
    End point description
    To achieve an ACR70 required at least a 70% improvement compared with baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 70% improvement in three of the following five additional measurements: •Physician's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's assessment of pain (assessed using a 100 mm VAS); •HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3; •Acute phase reactant: CRP or, if CRP was missing, ESR. Participants who withdrew prematurely from the study prior to Week 48, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders. ITT Population
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    172
    167
    170
    Units: Percentage of Participants
        number (not applicable)
    9.3
    12.6
    13.5
    No statistical analyses for this end point

    Post-hoc: Time to Repletion of Peripheral CD19+ B-cells

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    End point title
    Time to Repletion of Peripheral CD19+ B-cells
    End point description
    Peripheral CD19+ B-cell repletion was defined as a CD19+ B-cell count that returned to the Baseline value or returned to ≥ the LLN, whichever was lower. ESFU Population
    End point type
    Post-hoc
    End point timeframe
    Beginning of the first infusion (Day 1) in the last treatment cycle until repletion or the end of the study (up to 3 years, 6 months)
    End point values
    Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX
    Number of subjects analysed
    80
    43
    Units: Weeks
        median (confidence interval 95%)
    110.3 (89.6 to 148.3)
    109.6 (94.1 to 134.9)
    No statistical analyses for this end point

    Post-hoc: Percentage of Participants With Low Immunoglobulin Concentrations Pre- and Post-Rituximab Treatment

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    End point title
    Percentage of Participants With Low Immunoglobulin Concentrations Pre- and Post-Rituximab Treatment
    End point description
    A low immunoglobulin concentration was defined as a concentration below the lower level of normal. Safety follow-up population.
    End point type
    Post-hoc
    End point timeframe
    Baseline (pre-rituximab), Beginning of the safety follow-up period to the end of the study (approximately 6 years) (post-rituximab)
    End point values
    Rituximab + MTX
    Number of subjects analysed
    491
    Units: Percentage of Participants
    number (not applicable)
        Pre-Rituximab (N=490)
    0.2
        Post-Rituximab (N=491)
    5.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 5.1 years after last dose in treatment period (treatment period = up to 5 years)
    Adverse event reporting additional description
    During the 5-year treatment period, all adverse events (AEs) regardless of seriousness were reported. During the standard 48-week safety follow-up (SFU) and extended safety follow-up (ESFU), all serious adverse events (SAEs) and all non-serious infections were reported.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Placebo + MTX
    Reporting group description
    Includes all data for participants who remained on placebo, and data up to the point of switch if the participant switched to treatment with rituximab. Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Reporting group title
    Rituximab 2 x 0.5 g + MTX
    Reporting group description
    Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Reporting group title
    Rituximab 2 x 1.0 g + MTX
    Reporting group description
    Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

    Reporting group title
    Switch Population: Placebo + MTX
    Reporting group description
    Includes all data up to the point of switch for participants in the Placebo + Methotrexate treatment group who switched to treatment with rituximab after Week 24.

    Reporting group title
    Switch Population: Rituximab
    Reporting group description
    Includes all data from the point of switch for participants who switched from Placebo + Methotrexate to treatment with rituximab.

    Reporting group title
    Rituximab 2 x 0.5 g + MTX - Extended Safety Follow-up Period
    Reporting group description
    Participants received no treatment during the extended safety follow-up period.

    Reporting group title
    Rituximab 2 x 1.0 g + MTX - Extended Safety Follow-up Period
    Reporting group description
    Participants received no treatment during the extended safety follow-up period.

    Serious adverse events
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX Switch Population: Placebo + MTX Switch Population: Rituximab Rituximab 2 x 0.5 g + MTX - Extended Safety Follow-up Period Rituximab 2 x 1.0 g + MTX - Extended Safety Follow-up Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 172 (9.30%)
    52 / 167 (31.14%)
    46 / 170 (27.06%)
    12 / 155 (7.74%)
    45 / 155 (29.03%)
    8 / 82 (9.76%)
    2 / 44 (4.55%)
         number of deaths (all causes)
    2
    6
    3
    0
    3
    3
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    1 / 155 (0.65%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung squamous cell carcinoma stage unspecified
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    T-cell prolymphocytic leukaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion threatened
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 167 (1.20%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibrosis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hernia obstructive
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal prolapse
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Testicular necrosis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 172 (0.58%)
    4 / 167 (2.40%)
    3 / 170 (1.76%)
    0 / 155 (0.00%)
    3 / 155 (1.94%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 3
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress fracture
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovial rupture
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic coma
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatitis B DNA increased
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    2 / 172 (1.16%)
    3 / 167 (1.80%)
    1 / 170 (0.59%)
    2 / 155 (1.29%)
    3 / 155 (1.94%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 8
    1 / 1
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 172 (0.00%)
    4 / 167 (2.40%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 167 (1.20%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    2 / 155 (1.29%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    1 / 155 (0.65%)
    3 / 155 (1.94%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Demyelination
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    1 / 155 (0.65%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign intracranial hypertension
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic hyperosmolar coma
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    2 / 170 (1.18%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    2 / 170 (1.18%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    1 / 155 (0.65%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    1 / 155 (0.65%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    2 / 170 (1.18%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    2 / 155 (1.29%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    2 / 170 (1.18%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    2 / 170 (1.18%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 167 (1.20%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral hernia, obstructive
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileal ulcer
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia, obstructive
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    1 / 155 (0.65%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 172 (1.16%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    1 / 155 (0.65%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 167 (1.20%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Lichen planus
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 172 (0.58%)
    4 / 167 (2.40%)
    5 / 170 (2.94%)
    1 / 155 (0.65%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 5
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 172 (0.58%)
    2 / 167 (1.20%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    2 / 155 (1.29%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondyloarthropathy
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Vertigo
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Goitre
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    2 / 170 (1.18%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 172 (0.58%)
    3 / 167 (1.80%)
    4 / 170 (2.35%)
    1 / 155 (0.65%)
    3 / 155 (1.94%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    4 / 5
    1 / 1
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 172 (1.16%)
    1 / 167 (0.60%)
    1 / 170 (0.59%)
    2 / 155 (1.29%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 1
    2 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 167 (1.80%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 167 (1.80%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 167 (1.20%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 167 (1.20%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 167 (1.20%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    1 / 82 (1.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    1 / 155 (0.65%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 167 (1.20%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess soft tissue
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 170 (0.59%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 170 (0.00%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX Switch Population: Placebo + MTX Switch Population: Rituximab Rituximab 2 x 0.5 g + MTX - Extended Safety Follow-up Period Rituximab 2 x 1.0 g + MTX - Extended Safety Follow-up Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 172 (65.12%)
    149 / 167 (89.22%)
    151 / 170 (88.82%)
    99 / 155 (63.87%)
    131 / 155 (84.52%)
    5 / 82 (6.10%)
    2 / 44 (4.55%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 172 (1.74%)
    28 / 167 (16.77%)
    18 / 170 (10.59%)
    2 / 155 (1.29%)
    15 / 155 (9.68%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    30
    21
    2
    19
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 172 (0.58%)
    13 / 167 (7.78%)
    11 / 170 (6.47%)
    0 / 155 (0.00%)
    8 / 155 (5.16%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    16
    13
    0
    8
    0
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 172 (1.16%)
    9 / 167 (5.39%)
    12 / 170 (7.06%)
    2 / 155 (1.29%)
    5 / 155 (3.23%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    11
    13
    2
    6
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 172 (4.07%)
    9 / 167 (5.39%)
    8 / 170 (4.71%)
    6 / 155 (3.87%)
    5 / 155 (3.23%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    7
    10
    8
    6
    7
    0
    0
    Depression
         subjects affected / exposed
    0 / 172 (0.00%)
    15 / 167 (8.98%)
    7 / 170 (4.12%)
    0 / 155 (0.00%)
    7 / 155 (4.52%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    16
    7
    0
    7
    0
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    33 / 172 (19.19%)
    59 / 167 (35.33%)
    59 / 170 (34.71%)
    28 / 155 (18.06%)
    39 / 155 (25.16%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    44
    160
    148
    38
    105
    0
    0
    Fall
         subjects affected / exposed
    5 / 172 (2.91%)
    14 / 167 (8.38%)
    5 / 170 (2.94%)
    4 / 155 (2.58%)
    18 / 155 (11.61%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    5
    22
    6
    4
    23
    0
    0
    Laceration
         subjects affected / exposed
    1 / 172 (0.58%)
    2 / 167 (1.20%)
    10 / 170 (5.88%)
    1 / 155 (0.65%)
    6 / 155 (3.87%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    2
    10
    1
    6
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 172 (4.07%)
    13 / 167 (7.78%)
    22 / 170 (12.94%)
    7 / 155 (4.52%)
    11 / 155 (7.10%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    7
    13
    25
    7
    15
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 172 (0.00%)
    6 / 167 (3.59%)
    10 / 170 (5.88%)
    0 / 155 (0.00%)
    6 / 155 (3.87%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    6
    11
    0
    6
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 172 (2.91%)
    9 / 167 (5.39%)
    12 / 170 (7.06%)
    4 / 155 (2.58%)
    7 / 155 (4.52%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    5
    9
    13
    4
    7
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 172 (3.49%)
    18 / 167 (10.78%)
    15 / 170 (8.82%)
    5 / 155 (3.23%)
    16 / 155 (10.32%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    6
    28
    21
    5
    24
    0
    0
    Dizziness
         subjects affected / exposed
    4 / 172 (2.33%)
    11 / 167 (6.59%)
    10 / 170 (5.88%)
    3 / 155 (1.94%)
    0 / 155 (0.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    4
    11
    11
    3
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 172 (1.16%)
    8 / 167 (4.79%)
    6 / 170 (3.53%)
    2 / 155 (1.29%)
    9 / 155 (5.81%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    9
    7
    2
    9
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 172 (4.07%)
    27 / 167 (16.17%)
    20 / 170 (11.76%)
    7 / 155 (4.52%)
    20 / 155 (12.90%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    8
    33
    30
    8
    26
    0
    0
    Nausea
         subjects affected / exposed
    4 / 172 (2.33%)
    21 / 167 (12.57%)
    17 / 170 (10.00%)
    4 / 155 (2.58%)
    12 / 155 (7.74%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    4
    22
    21
    4
    12
    0
    0
    Dyspepsia
         subjects affected / exposed
    3 / 172 (1.74%)
    4 / 167 (2.40%)
    4 / 170 (2.35%)
    3 / 155 (1.94%)
    11 / 155 (7.10%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    4
    6
    3
    12
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 172 (1.16%)
    7 / 167 (4.19%)
    10 / 170 (5.88%)
    2 / 155 (1.29%)
    4 / 155 (2.58%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    8
    10
    2
    4
    0
    0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    2 / 172 (1.16%)
    8 / 167 (4.79%)
    7 / 170 (4.12%)
    2 / 155 (1.29%)
    8 / 155 (5.16%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    12
    9
    2
    9
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 172 (0.58%)
    9 / 167 (5.39%)
    7 / 170 (4.12%)
    1 / 155 (0.65%)
    6 / 155 (3.87%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    12
    8
    1
    6
    0
    0
    Alopecia
         subjects affected / exposed
    1 / 172 (0.58%)
    9 / 167 (5.39%)
    6 / 170 (3.53%)
    0 / 155 (0.00%)
    3 / 155 (1.94%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    10
    6
    0
    3
    0
    0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    30 / 172 (17.44%)
    49 / 167 (29.34%)
    36 / 170 (21.18%)
    26 / 155 (16.77%)
    31 / 155 (20.00%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    42
    71
    49
    38
    49
    0
    0
    Back pain
         subjects affected / exposed
    3 / 172 (1.74%)
    22 / 167 (13.17%)
    14 / 170 (8.24%)
    3 / 155 (1.94%)
    10 / 155 (6.45%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    28
    18
    3
    10
    0
    0
    Arthralgia
         subjects affected / exposed
    3 / 172 (1.74%)
    9 / 167 (5.39%)
    15 / 170 (8.82%)
    2 / 155 (1.29%)
    7 / 155 (4.52%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    16
    22
    2
    8
    0
    0
    Muscle spasms
         subjects affected / exposed
    4 / 172 (2.33%)
    7 / 167 (4.19%)
    7 / 170 (4.12%)
    4 / 155 (2.58%)
    10 / 155 (6.45%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    4
    9
    7
    4
    14
    0
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 172 (0.58%)
    8 / 167 (4.79%)
    10 / 170 (5.88%)
    1 / 155 (0.65%)
    8 / 155 (5.16%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    12
    10
    1
    8
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 172 (0.58%)
    9 / 167 (5.39%)
    9 / 170 (5.29%)
    1 / 155 (0.65%)
    7 / 155 (4.52%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    11
    10
    1
    8
    0
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    4 / 172 (2.33%)
    13 / 167 (7.78%)
    6 / 170 (3.53%)
    3 / 155 (1.94%)
    7 / 155 (4.52%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    4
    14
    6
    3
    8
    0
    0
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 172 (0.58%)
    7 / 167 (4.19%)
    9 / 170 (5.29%)
    1 / 155 (0.65%)
    5 / 155 (3.23%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    7
    9
    1
    6
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 172 (7.56%)
    59 / 167 (35.33%)
    50 / 170 (29.41%)
    13 / 155 (8.39%)
    39 / 155 (25.16%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    14
    100
    84
    14
    74
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    17 / 172 (9.88%)
    43 / 167 (25.75%)
    42 / 170 (24.71%)
    16 / 155 (10.32%)
    34 / 155 (21.94%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    22
    82
    77
    20
    61
    0
    0
    Urinary tract infection
         subjects affected / exposed
    12 / 172 (6.98%)
    41 / 167 (24.55%)
    25 / 170 (14.71%)
    9 / 155 (5.81%)
    34 / 155 (21.94%)
    5 / 82 (6.10%)
    2 / 44 (4.55%)
         occurrences all number
    23
    72
    45
    10
    50
    7
    3
    Sinusitis
         subjects affected / exposed
    6 / 172 (3.49%)
    24 / 167 (14.37%)
    21 / 170 (12.35%)
    6 / 155 (3.87%)
    29 / 155 (18.71%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    6
    39
    36
    6
    46
    0
    0
    Bronchitis
         subjects affected / exposed
    3 / 172 (1.74%)
    27 / 167 (16.17%)
    25 / 170 (14.71%)
    2 / 155 (1.29%)
    24 / 155 (15.48%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    39
    30
    2
    37
    0
    0
    Gastroenteritis
         subjects affected / exposed
    8 / 172 (4.65%)
    15 / 167 (8.98%)
    14 / 170 (8.24%)
    7 / 155 (4.52%)
    17 / 155 (10.97%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    8
    16
    17
    7
    23
    0
    0
    Pharyngitis
         subjects affected / exposed
    10 / 172 (5.81%)
    15 / 167 (8.98%)
    11 / 170 (6.47%)
    10 / 155 (6.45%)
    9 / 155 (5.81%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    10
    17
    13
    10
    10
    0
    0
    Influenza
         subjects affected / exposed
    1 / 172 (0.58%)
    17 / 167 (10.18%)
    20 / 170 (11.76%)
    1 / 155 (0.65%)
    13 / 155 (8.39%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    26
    30
    1
    15
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 172 (0.00%)
    9 / 167 (5.39%)
    8 / 170 (4.71%)
    0 / 155 (0.00%)
    7 / 155 (4.52%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    12
    9
    0
    7
    0
    0
    Herpes zoster
         subjects affected / exposed
    2 / 172 (1.16%)
    10 / 167 (5.99%)
    4 / 170 (2.35%)
    2 / 155 (1.29%)
    5 / 155 (3.23%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    10
    4
    2
    5
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 172 (0.58%)
    2 / 167 (1.20%)
    8 / 170 (4.71%)
    1 / 155 (0.65%)
    9 / 155 (5.81%)
    0 / 82 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    3
    17
    1
    19
    0
    0

    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
    The first amendment, B, made three main changes: 1. Correction of the dose of pre-infusion antihistamine from diphenhydramine 100 mg to diphenhydramine 50 mg (or equivalent), in accordance with clinical practice. 2. Removal of immunoglobulin concentrations from the eligibility criteria for retreatment. 3. Extended the screening period to 42 days for participants requiring vaccination. The other items were minor changes, clarifications and corrections that did not affect the study conduct.
    22 Mar 2007
    The second amendment, C, made the following changes: 1. The addition of a comparison of the efficacy of two courses of 2 x 0.5 g rituximab with two courses of 2 x 1.0 g rituximab. This required the addition of study objective No. 3: “to explore a dose separation of rituximab 0.5 g IV x 2 from rituximab 1.0 g IV x 2 at Week 48”, and additions to the assessments and statistical analysis sections. Blinding was extended from Week 24 to Week 48; i.e., although after Week 24 all retreatment infusions were of rituximab, investigators, participants, and study team remained blinded to the dose, and also to the previous first course of treatment. 2. Hepatitis monitoring was added for Hepatitis B core antigen (HBcAg)-positive participants who might have been admitted to the study if they were Hepatitis surface antigen (HBsAb)-negative (HBsAb-positive participants were excluded from the study). Further courses of rituximab for these participants would only be allowed if their hepatitis B viral load was negative and their aspartate aminotransferase (AST) or alanine aminotransferase (ALT) were ≤2.5 x the upper limit of normal (ULN). 3. The rituximab warnings and precautions were updated in line with the latest Investigator’s Brochure. 4. The assessment of eligibility for retreatment was clarified, especially the timing of assessment and the maximum time from assessment to initiation of retreatment. 5. Addition of the proportion of participants with a minimal clinically important difference (MCID) in the health assessment questionnaire (HAQ) as a secondary endpoint. The other changes including corrections, updates and clarifications did not affect the study conduct.
    19 Nov 2008
    The third amendment, D, made the following changes: 1. Extension of study to provide additional information on the safety of long-term treatment with rituximab in RA participants. 2. Update to safety information (including PML update). 3. Update of study procedures.
    31 Aug 2012
    The fourth amendment, E, made the following changes: 1. Discontinuation of extended B-cell follow up following the safety follow-up period. 2. Administrative updates.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/20488885
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