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    Clinical Trial Results:
    A RANDOMIZED, DOUBLE-BLIND, STUDY COMPARING THE PHARMACOKINETICS AND PHARMACODYNAMICS, AND ASSESSING THE SAFETY OF PF-05280586 AND RITUXIMAB IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS ON A BACKGROUND OF METHOTREXATE WHO HAVE HAD AN INADEQUATE RESPONSE TO ONE OR MORE TNF ANTAGONIST THERAPIES

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2011-002896-40
    Trial protocol
    		 GB   ES   DE   PL  
    Global end of trial date
    07 May 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 May 2016
    First version publication date
    02 Aug 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • New data added to full data set
    reporting periods and duplicate AEs in their data

    Trial information

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    Trial identification
    Sponsor protocol code
    B3281001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01526057
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021,
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021,
    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
    07 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the pharmacokinetic (PK) similarity of rituximab-Pfizer, the rituximab product MabThera (licensed for use in the European Union [EU], hereafter referred to as rituximab-EU) and the rituximab product Rituxan (licensed for use in the United States [US], hereafter referred to as rituximab-US) in participants with active rheumatoid arthritis (RA) on a background of methotrexate (MTX) who have had an inadequate response to 1 or more tumour necrosis factor (TNF) antagonist therapies.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants. Safety monitoring was performed throughout the study by an independent data monitoring committee (DMC) at approximately 3-month intervals unless safety concerns requiring their attention arose earlier. In addition, early in the study, an internal review committee monitored safety at monthly intervals for approximately the first 10 months of the study.
    Background therapy
    		 Methotrexate (MTX)
    Evidence for comparator
    		 The mechanism of action of rituximab, which results in profound and prolonged B-cell depletion, precludes the conduct of PK studies in healthy volunteer participants. The population studied in this clinical trial included participants with active RA who were receiving background therapy with MTX and had an inadequate response to 1 or more TNF antagonist therapies. Participants might have been exposed to other biologics, with the exception of any B-cell intervention. This study population reflects the approved, labelled indication for MabThera and Rituxan. Therefore, the treatment regimen provided in the rituximab product labelling was used in the study: 1000 mg rituximab-Pfizer, rituximab-EU, or rituximab-US administered as an intravenous (IV) infusion on Days 1 and 15.
    Actual start date of recruitment
    30 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Colombia: 13
    Country: Number of subjects enrolled
    Swaziland: 8
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    United States: 150
    Worldwide total number of subjects
    220
    EEA total number of subjects
    4
    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)
    178
    From 65 to 84 years
    42
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multinational, randomised, double-blind, controlled trial in participants with active RA on a background of MTX. The study was conducted at 56 centres in 10 countries. There were a total of 220 participants enrolled in this study: 73 in the rituximab-US arm, 74 in the rituximab-EU arm, and 73 in the rituximab-Pfizer arm.

    Pre-assignment
    Screening details
    		 Participants were screened for up to 4 weeks prior to randomisation.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Study blinded to participant, investigator/study staff, sponsor’s study team conducting trial. The study pharmacists preparing treatment infusions were unblinded. The Independent Review Committee and DMC reviewed partially blinded results (ie, treatment groups identified as Arms A, B, and C). Blinding broken in emergency situations when knowledge of treatment assignment was required for medical management for individual subject safety. The investigator notified the sponsor before breaking blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab-Pfizer
    Arm description
    		 Rituximab-Pfizer group received IV rituximab (PF-05280586) infusion 1000 milligrams (mg) per (/) 500 millilitres (mL) (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-05280586 (Rituximab-Pfizer)
    Investigational medicinal product code
    Other name
    Rituximab-Pfizer
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered at a dose of 1000 mg/500 mL on study Days 1 and 15. The infusion rate was followed as per the guidance as presented in the protocol. The minimum duration required to deliver rituximab 1000 mg during the first infusion for each subject was 4.25 hours. The minimum duration for the second infusion was 3.25 hours. When the drug product administration was complete, a 3.33 mL/minute flush with diluent for 10 minutes was performed. Infusions could have been longer if infusion interruption or rate reduction was necessary to manage acute infusion reactions.

    Arm title
    		 Rituximab-EU
    Arm description
    		 Rituximab-EU group received IV rituximab (MabThera) infusion 1000 mg/500 mL (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab - EU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered at a dose of 1000 mg/500 mL on study Days 1 and 15. The infusion rate was followed as per the guidance as presented in the protocol. The minimum duration required to deliver rituximab 1000 mg during the first infusion for each subject was 4.25 hours. The minimum duration for the second infusion was 3.25 hours. When the drug product administration was complete, a 3.33 mL/minute flush with diluent for 10 minutes was performed. Infusions could have been longer if infusion interruption or rate reduction was necessary to manage acute infusion reactions.

    Arm title
    		 Rituximab-US
    Arm description
    		 Rituximab-US group received IV rituximab (Rituxan) infusion 1000 mg/500 mL (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab - US
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered at a dose of 1000 mg/500 mL on study Days 1 and 15. The infusion rate was followed as per the guidance as presented in the protocol. The minimum duration required to deliver rituximab 1000 mg during the first infusion for each subject was 4.25 hours. The minimum duration for the second infusion was 3.25 hours. When the drug product administration was complete, a 3.33 mL/minute flush with diluent for 10 minutes was performed. Infusions could have been longer if infusion interruption or rate reduction was necessary to manage acute infusion reactions.

    Number of subjects in period 1
    		Rituximab-Pfizer Rituximab-EU Rituximab-US
    Started
    73
    74
    73
    Completed
    64
    71
    67
    Not completed
    9
    3
    6
         Adverse event, serious fatal
    1
    -
    -
         Consent withdrawn by subject
    3
    2
    2
         Adverse event, non-fatal
    3
    1
    1
         Other
    1
    -
    1
         Lost to follow-up
    1
    -
    1
         Protocol deviation
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab-Pfizer
    Reporting group description
    		 Rituximab-Pfizer group received IV rituximab (PF-05280586) infusion 1000 milligrams (mg) per (/) 500 millilitres (mL) (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.

    Reporting group title
    Rituximab-EU
    Reporting group description
    		 Rituximab-EU group received IV rituximab (MabThera) infusion 1000 mg/500 mL (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.

    Reporting group title
    Rituximab-US
    Reporting group description
    		 Rituximab-US group received IV rituximab (Rituxan) infusion 1000 mg/500 mL (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.

    Reporting group values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US Total
    Number of subjects
    		 73 74 73 220
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.9 ± 11.52 54.9 ± 11.07 53.4 ± 11.87 -
    Gender categorical
    Units: Subjects
        Female
    		 59 57 54 170
        Male
    		 14 17 19 50

    End points

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    End points reporting groups
    Reporting group title
    Rituximab-Pfizer
    Reporting group description
    		 Rituximab-Pfizer group received IV rituximab (PF-05280586) infusion 1000 milligrams (mg) per (/) 500 millilitres (mL) (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.

    Reporting group title
    Rituximab-EU
    Reporting group description
    		 Rituximab-EU group received IV rituximab (MabThera) infusion 1000 mg/500 mL (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.

    Reporting group title
    Rituximab-US
    Reporting group description
    		 Rituximab-US group received IV rituximab (Rituxan) infusion 1000 mg/500 mL (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.

    Primary: Maximum Serum Concentration (Cmax) of Rituximab

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    End point title
    		 Maximum Serum Concentration (Cmax) of Rituximab
    End point description
    Cmax is the peak serum concentration of study drug (rituximab) after a dose has been administered. Per protocol (PP) population: all participants who were randomized, received the full doses of the assigned study treatment, and had no major protocol violations that could impact the PK analysis. Exclusions from the PP population were based on a blinded data review by the Medical Monitor and Clinical Pharmacologist.
    End point type
    Primary
    End point timeframe
    Predose (Day 1) and 3, 4.25 (immediately before 1st infusion end), 72, 168, 335 (Day 15 within 1.5 hours before 2nd infusion), 337.5, 339.25 (Day 15 immediately before 2nd infusion end), 408, 504, 672, 1344, and 2016 hours after start of 1st infusion
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    68
    67
    63
    Units: ug/mL
        arithmetic mean (standard deviation)
    453 ± 153
    422 ± 111
    430 ± 163
    Statistical analysis title
    		 Rituximab-Pfizer, Rituximab-EU
    Statistical analysis description
    A 90% confidence interval (CI) on the estimated difference between 2 treatment groups was constructed using a 1-way analysis of variance (ANOVA) model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-EU v Rituximab-Pfizer
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    105.67
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 96.91
         upper limit
    		 115.21
    Notes
    [1] - PK similarity for a given test-to-reference comparison would be demonstrated if the 90% CI for the test-to reference ratios in Cmax and area under the serum concentration-time curve (AUC) from time 0 extrapolated to infinite time (AUC 0-inf) are within the 80.00% to 125.00% range. Rituximab-Pfizer is the numerator.
    Statistical analysis title
    		 Rituximab-Pfizer, Rituximab-US
    Statistical analysis description
    A 90% CI on the estimated difference between 2 treatment groups was constructed using a 1-way ANOVA model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-Pfizer v Rituximab-US
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    106.62
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 97.65
         upper limit
    		 116.41
    Notes
    [2] - PK similarity for a given test-to-reference comparison would be demonstrated if the 90% CI for the test-to reference ratios in Cmax and AUC 0-inf are within the 80.00% to 125.00% range. Rituximab-Pfizer is the numerator.
    Statistical analysis title
    		 Rituximab-EU, Rituximab-US
    Statistical analysis description
    A 90% CI on the estimated difference between 2 treatment groups was constructed using a 1-way ANOVA model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-EU v Rituximab-US
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    		 ANOVA
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    100.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 92.38
         upper limit
    		 110.2
    Notes
    [3] - PK similarity for a given test-to-reference comparison would be demonstrated if the 90% CI for the test-to reference ratios in Cmax and AUC 0-inf are within the 80.00% to 125.00% range. Rituximab-EU is the numerator.

    Primary: AUC 0-inf of Rituximab

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    End point title
    		 AUC 0-inf of Rituximab
    End point description
    The AUC 0-inf refers to the concentration in serum of the drug over time. It represents the total drug exposure over time, from time 0 (the point of drug administration) extrapolated to infinity. PP Population
    End point type
    Primary
    End point timeframe
    Predose (Day 1) and 3, 4.25 (immediately before 1st infusion end), 72, 168, 335 (Day 15 within 1.5 hours before 2nd infusion), 337.5, 339.25 (Day 15 immediately before 2nd infusion end), 408, 504, 672, 1344, and 2016 hours after start of 1st infusion
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    68
    67
    62
    Units: ug/mL/hour
        arithmetic mean (standard deviation)
    213000 ± 90400
    200000 ± 74600
    214000 ± 95300
    Statistical analysis title
    		 Rituximab-Pfizer, Rituximab-EU
    Statistical analysis description
    A 90% CI on the estimated difference between 2 treatment groups was constructed using a 1-way ANOVA model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-Pfizer v Rituximab-EU
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    104.19
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 92.75
         upper limit
    		 117.06
    Notes
    [4] - PK similarity for a given test-to-reference comparison would be demonstrated if the 90% CI for the test-to reference ratios in Cmax and AUC 0-inf are within the 80.00% to 125.00% range. Rituximab-Pfizer is the numerator. For AUC 0-inf calculated after inclusion of additional drug concentration samples collected on Day 169, the ratio (90% CI for ratio) was 104.19 (92.83, 116.93).
    Statistical analysis title
    		 Rituximab-Pfizer, Rituximab-US
    Statistical analysis description
    A 90% CI on the estimated difference between 2 treatment groups was constructed using a 1-way ANOVA model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-Pfizer v Rituximab-US
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    100.45
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 89.2
         upper limit
    		 113.11
    Notes
    [5] - PK similarity for a given test-to-reference comparison would be demonstrated if the 90% CI for the test-to reference ratios in Cmax and AUC 0-inf are within the 80.00% to 125.00% range. Rituximab-Pfizer is the numerator. For AUC 0-inf calculated after inclusion of additional drug concentration samples collected on Day 169, the ratio (90% CI for ratio) was 100.21 (89.12, 112.67).
    Statistical analysis title
    		 Rituximab-EU, Rituximab-US
    Statistical analysis description
    A 90% CI on the estimated difference between 2 treatment groups was constructed using a 1-way ANOVA model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-EU v Rituximab-US
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    96.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 85.57
         upper limit
    		 108.6
    Notes
    [6] - PK similarity for a given test-to-reference comparison would be demonstrated if the 90% CI for the test-to reference ratios in Cmax and AUC 0-inf are within the 80.00% to 125.00% range. Rituximab-EU is the numerator. For AUC 0-inf calculated after inclusion of additional drug concentration samples collected on Day 169, the ratio (90% CI for ratio) was 96.18 (85.51, 108.19).

    Secondary: Rituximab AUC From Time 0 to 2 Weeks (AUC 0-2wk)

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    End point title
    		 Rituximab AUC From Time 0 to 2 Weeks (AUC 0-2wk)
    End point description
    The AUC 0-2wk refers to the concentration in serum of the drug over time. It represents the total drug exposure over time, from time 0 (the point of drug administration) to 2 weeks after drug administration. PP Population
    End point type
    Secondary
    End point timeframe
    Predose (Day 1) and 3, 4.25 (immediately before 1st infusion end), 72, 168, 335 (Day 15 within 1.5 hours before 2nd infusion), 337.5, 339.25 (Day 15 immediately before 2nd infusion end), 408, 504, 672, 1344, and 2016 hours after start of 1st infusion
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    68
    67
    63
    Units: ug/mL/hour
        arithmetic mean (standard deviation)
    52100 ± 18000
    49600 ± 14200
    49200 ± 15900
    Statistical analysis title
    		 Rituximab-Pfizer, Rituximab EU
    Statistical analysis description
    A 90% CI on the estimated difference between 2 treatment groups was constructed using a 1-way ANOVA model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-Pfizer v Rituximab-EU
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    103.74
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 95.1
         upper limit
    		 113.15
    Notes
    [7] - Rituximab-Pfizer is the numerator.
    Statistical analysis title
    		 Rituximab-Pfizer, Rituximab-US
    Statistical analysis description
    A 90% CI on the estimated difference between 2 treatment groups was constructed using a 1-way ANOVA model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-Pfizer v Rituximab-US
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    105.56
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 96.64
         upper limit
    		 115.3
    Notes
    [8] - Rituximab-Pfizer is the numerator.
    Statistical analysis title
    		 Rituximab-EU, Rituximab-US
    Statistical analysis description
    A 90% CI on the estimated difference between 2 treatment groups was constructed using a 1-way ANOVA model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-EU v Rituximab-US
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    101.76
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 93.13
         upper limit
    		 111.18
    Notes
    [9] - Rituximab-EU is the numerator.

    Secondary: Rituximab AUC From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-T)

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    End point title
    		 Rituximab AUC From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-T)
    End point description
    The AUC 0-T refers to the concentration in serum of the drug over time. It represents the total drug exposure over time, from time 0 (the point of drug administration) to the last measured concentration at time T. PP Population
    End point type
    Secondary
    End point timeframe
    Predose (Day 1) and 3, 4.25 (immediately before 1st infusion end), 72, 168, 335 (Day 15 within 1.5 hours before 2nd infusion), 337.5, 339.25 (Day 15 immediately before 2nd infusion end), 408, 504, 672, 1344, and 2016 hours after start of 1st infusion
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    68
    67
    63
    Units: ug/mL/hour
        arithmetic mean (standard deviation)
    198000 ± 79600
    188000 ± 64300
    196000 ± 78300
    Statistical analysis title
    		 Rituximab-Pfizer, Rituximab-EU
    Statistical analysis description
    A 90% CI on the estimated difference between 2 treatment groups was constructed using a 1-way ANOVA model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-Pfizer v Rituximab-EU
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    103.36
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 92.81
         upper limit
    		 115.12
    Notes
    [10] - Rituximab-Pfizer is the numerator. For AUC 0-T calculated after inclusion of the additional drug concentration samples collected on Day 169, the ratio (90% CI for ratio) was 103.26 (92.13, 115.73).
    Statistical analysis title
    		 Rituximab-Pfizer, Rituximab-US
    Statistical analysis description
    A 90% CI on the estimated difference between 2 treatment groups was constructed using a 1-way ANOVA model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-Pfizer v Rituximab-US
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    101.33
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 90.82
         upper limit
    		 113.04
    Notes
    [11] - Rituximab-Pfizer is the numerator. For AUC 0-T calculated after inclusion of the additional drug concentration samples collected on Day 169, the ratio (90% CI for ratio) was 100.45 (89.46, 112.79).
    Statistical analysis title
    		 Rituximab-US, Rituximab-EU
    Statistical analysis description
    A 90% CI on the estimated difference between 2 treatment groups was constructed using a 1-way ANOVA model based on natural log-transformed data. The estimated differences for the log-transformed PK parameters were then transformed to relative ratios of PK parameters by exponentiation.
    Comparison groups
    Rituximab-US v Rituximab-EU
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    Parameter type
    		 Test-to-reference ratio: adjusted means
    Point estimate
    98.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 87.83
         upper limit
    		 109.4
    Notes
    [12] - Rituximab-EU is the numerator. For AUC0- T calculated after inclusion of the additional drug concentration samples collected on Day 169, the ratio (90% CI for ratio) was 97.28 (86.60, 109.27).

    Secondary: Cluster of Differentiation 19 (CD19+) B-cell Count AUC From Time 0 to the Last Measurement at Time T (AUC 0-T,B-cell)

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    End point title
    		 Cluster of Differentiation 19 (CD19+) B-cell Count AUC From Time 0 to the Last Measurement at Time T (AUC 0-T,B-cell)
    End point description
    The AUC 0-T,B-cell refers to the concentration in serum of B-cells. It represents the total B-cells over time from time 0 (the point of drug administration) to the last measurement taken at time T. Modified intention-to-treat (mITT) population, defined as all participants who were randomised and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (end of trial [EOT])
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    68
    69
    67
    Units: cells/day/mL
        arithmetic mean (standard deviation)
    13312 ± 13309
    14304 ± 13146
    12496 ± 13500
    No statistical analyses for this end point

    Secondary: Minimum Post-Baseline CD19+ B-cell Count

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    End point title
    		 Minimum Post-Baseline CD19+ B-cell Count
    End point description
    The lowest CD19+ B-cell count measured in a participant's blood post-baseline. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    68
    69
    67
    Units: /uL
        arithmetic mean (standard deviation)
    0 ± 0.28
    0 ± 0
    0 ± 0.18
    No statistical analyses for this end point

    Secondary: Time to Minimum Post-Baseline CD19+ B-cell Count

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    End point title
    		 Time to Minimum Post-Baseline CD19+ B-cell Count
    End point description
    The amount of time in weeks from baseline to the lowest observed CD19+ B-cell count. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    68
    69
    67
    Units: weeks
        arithmetic mean (standard deviation)
    1.4 ± 1.41
    1.6 ± 1.68
    1.5 ± 1.31
    No statistical analyses for this end point

    Secondary: Duration of B-cell depletion (τB-cell)

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    End point title
    		 Duration of B-cell depletion (τB-cell)
    End point description
    The τB-cell is defined as the time interval over which the B-cell count was <0.3 cells/microliter (uL) or the detection limit. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    68
    69
    67
    Units: days
        arithmetic mean (standard deviation)
    126 ± 41.8
    123 ± 38.6
    120 ± 40.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants with CD19+ B-cell Count Recovery

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    End point title
    		 Percentage of Participants with CD19+ B-cell Count Recovery
    End point description
    The percentage of participants with CD19+ B-cell counts which fell to <50% of Baseline value during treatment and which recovered to ≥50% of Baseline value at EOT. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    68
    69
    67
    Units: Percentage of Participants
        number (not applicable)
    4.4
    8.7
    9
    No statistical analyses for this end point

    Secondary: Area under the CD19+ B-cell count concentration-time profile (AUC 0-T, B-cell)

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    End point title
    		 Area under the CD19+ B-cell count concentration-time profile (AUC 0-T, B-cell)
    End point description
    The AUC 0-T, B-cell refers to the CD19+ B-cell count over time. It represents the total B-cells over time, from time 0 (the point of drug administration) to the last measured count at time T.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT). mITT population.
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    68
    69
    67
    Units: days/cells/uL
        arithmetic mean (standard deviation)
    13312.1 ± 13309.15
    14304.2 ± 13145.72
    12495.9 ± 13499.97
    No statistical analyses for this end point

    Secondary: Baseline and Change from Baseline in Circulating Immunoglobulin-M (IgM) by Visit

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    End point title
    		 Baseline and Change from Baseline in Circulating Immunoglobulin-M (IgM) by Visit
    End point description
    The level of IgM in serum at Baseline and the change from Baseline at each subsequent visit. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: g/L
    arithmetic mean (standard deviation)
        Baseline (n=73,74,73)
    1.381 ± 0.7617
    1.46 ± 0.8076
    1.394 ± 0.8372
        Change from Baseline at Week 1 (n=71,69,70)
    0 ± 0.15
    0 ± 0.17
    0 ± 0.19
        Change from Baseline at Week 2 (n=71,72,68)
    0 ± 0.17
    0 ± 0.17
    0 ± 0.2
        Change from Baseline at Week 3 (n=71,74,69)
    -0.1 ± 0.18
    -0.1 ± 0.17
    0 ± 0.15
        Change from Baseline at Week 4 (n=68,69,68)
    -0.1 ± 0.27
    -0.1 ± 0.2
    0 ± 0.33
        Change from Baseline at Week 5 (n=72,71,69)
    -0.1 ± 0.3
    -0.1 ± 0.26
    -0.1 ± 0.23
        Change from Baseline at Week 9 (n=68,73,70)
    -0.2 ± 0.32
    -0.3 ± 0.27
    -0.2 ± 0.28
        Change from Baseline at Week 13 (n=67,72,67)
    -0.2 ± 0.52
    -0.3 ± 0.3
    -0.2 ± 0.55
        Change from Baseline at Week 17 (n=67,71,67)
    -0.1 ± 0.92
    -0.3 ± 0.34
    -0.3 ± 0.34
        Change from Baseline at Week 21 (n=60,65,60)
    -0.3 ± 0.42
    -0.4 ± 0.33
    -0.3 ± 0.35
        Change from Baseline at Week 25 (EOT; n=50,57,55)
    -0.4 ± 0.42
    -0.3 ± 0.3
    -0.3 ± 0.48
    No statistical analyses for this end point

    Secondary: Percent (%) Change from Baseline in Circulating IgM by Visit

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    End point title
    		 Percent (%) Change from Baseline in Circulating IgM by Visit
    End point description
    The percentage change from Baseline in circulating IgM by visit. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    72
    74
    70
    Units: g/L
    arithmetic mean (standard deviation)
        Week 1 (n=71,69,70)
    3.3 ± 18.62
    1.4 ± 9.57
    -0.5 ± 9.93
        Week 2 (n=71,72,68)
    0.1 ± 12.45
    -0.3 ± 9.42
    0.7 ± 14.06
        Week 3 (n=71,74,69)
    -3.4 ± 12.98
    -4.9 ± 9.95
    -2.7 ± 9.82
        Week 4 (n=68,69,68)
    -5.5 ± 14.77
    -5 ± 10.59
    -2.2 ± 21.89
        Week 5 (n=72,71,69)
    -8.6 ± 16
    -7.9 ± 15.6
    -5.6 ± 14.39
        Week 9 (n=68,73,70)
    -14.4 ± 13.68
    -16.9 ± 13.69
    -14.1 ± 13.73
        Week 13 (n=67,72,67)
    -11.5 ± 37.17
    -22.2 ± 13.92
    -16.2 ± 30.14
        Week 17 (n=67,71,67)
    5.5 ± 226.39
    -23.7 ± 16.35
    -21.6 ± 14.88
        Week 21 (n=60,65,60)
    -21.6 ± 17.72
    -24.7 ± 21
    -21.3 ± 15.69
        Week 25 (EOT; n=50,57,55)
    -24.2 ± 14.63
    -21 ± 16.95
    -20.5 ± 21.78
    No statistical analyses for this end point

    Secondary: Percentage of Participants with American College of Rheumatology (ACR) 20% Improvement (ACR20) Response by Visit

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    End point title
    		 Percentage of Participants with American College of Rheumatology (ACR) 20% Improvement (ACR20) Response by Visit
    End point description
    ACR20 response: greater than or equal to (≥)20% improvement in tender joint count; ≥20% improvement in swollen joint count; and ≥20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP). Non-responder imputation categorised participants as having a non-response if they did not have data available at a visit due to missing data or study discontinuation. Participants who rolled over to the extension study were not included in the non-responder imputation from that point on. mITT population.
    End point type
    Secondary
    End point timeframe
    Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: Percentage of Participants
    number (not applicable)
        Week 3 (n=73,74,73)
    34.2
    33.8
    32.9
        Week 5 (n=73,74,73)
    54.8
    56.8
    42.5
        Week 9 (n=73,74,73)
    49.3
    60.8
    58.9
        Week 13 (n=73,74,73)
    50.7
    70.3
    63
        Week 17 (n=73,74,73)
    54.8
    67.6
    67.1
        Week 21 (n=72,74,72)
    54.2
    62.2
    69.4
        Week 25 (EOT; n=62,63,62)
    50
    60.3
    71
    No statistical analyses for this end point

    Secondary: Percentage of Participants with ACR 70% Improvement (ACR70) Response by Visit

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    End point title
    		 Percentage of Participants with ACR 70% Improvement (ACR70) Response by Visit
    End point description
    ACR70 response: ≥70% improvement in tender joint count; ≥70% improvement in swollen joint count; and ≥70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP. Non-responder imputation categorised participants as having a non-response if they did not have data available at a visit due to missing data or study discontinuation. Participants who rolled over to the extension study were not included in the non-responder imputation from that point on. mITT population.
    End point type
    Secondary
    End point timeframe
    Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: Percentage of Participants
    number (not applicable)
        Week 3 (n=73,74,73)
    2.7
    2.7
    2.7
        Week 5 (n=73,74,73)
    6.8
    6.8
    8.2
        Week 9 (n=73,74,73)
    12.3
    17.6
    16.4
        Week 13 (n=73,74,73)
    19.2
    28.4
    20.5
        Week 17 (n=73,74,73)
    15.1
    18.9
    19.2
        Week 21 (n=72,74,72)
    13.9
    23
    20.8
        Week 25 (EOT; n=62,63,62)
    16.1
    17.5
    19.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants with ACR 50% Improvement (ACR50) Response by Visit

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    End point title
    		 Percentage of Participants with ACR 50% Improvement (ACR50) Response by Visit
    End point description
    ACR50 response: ≥50% improvement in tender joint count; ≥50% improvement in swollen joint count; and ≥50% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP. Non-responder imputation categorized participants as having a non-response if they did not have data available at a visit due to missing data or study discontinuation. Participants who rolled over to the extension study were not included in the non-responder imputation from that point on. mITT population.
    End point type
    Secondary
    End point timeframe
    Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: Percentage of Participants
    number (not applicable)
        Week 3 (n=73,74,73)
    8.2
    5.4
    9.6
        Week 5 (n=73,74,73)
    19.2
    16.2
    20.5
        Week 9 (n=73,74,73)
    21.9
    32.4
    35.6
        Week 13 (n=73,74,73)
    35.6
    40.5
    31.5
        Week 17 (n=73,74,73)
    24.7
    36.5
    37
        Week 21 (n=72,74,72)
    27.8
    37.8
    38.9
        Week 25 (EOT; n=62,63,62)
    21
    38.1
    33.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants by Anti-drug Antibody (ADA) Status

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    End point title
    		 Percentage of Participants by Anti-drug Antibody (ADA) Status
    End point description
    Presence of anti-rituximab antibodies in blood. Participants with a positive antibody status at any time during the study were defined as having overall positive antibody status; participants with a negative antibody status throughout the study were defined as having overall negative antibody status. mITT populations.
    End point type
    Secondary
    End point timeframe
    Days 1 (pre-dose), 15 (prior to infusion), 29, 57, 85, and 169.
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: Percentage of Participants
        number (not applicable)
    9.6
    13.5
    12.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Neutralizing Antibody (NAb) in Participants with a Positive ADA by Visit

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    End point title
    		 Percentage of Participants with Neutralizing Antibody (NAb) in Participants with a Positive ADA by Visit
    End point description
    mITT population. Only participants with a positive ADA status were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Days 1 (pre-dose), 15 (prior to infusion), 29, 57, 85, and 169.
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    35
    39
    34
    Units: Percentage of participants
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Baseline and Change from Baseline in Disease Activity Score Based on 28-Joint Count and CRP (DAS28-CRP)

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    End point title
    		 Baseline and Change from Baseline in Disease Activity Score Based on 28-Joint Count and CRP (DAS28-CRP)
    End point description
    DAS28-CRP was calculated from the swollen joint count and tender joint count using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-CRP less than or equal to (≤) 3.2 implied low disease activity, DAS28-CRP greater than (>)3.2 to ≤5.1 implied moderate to high disease activity, and DAS28-CRP less than (<)2.6 implied remission. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=73,74,73)
    5.6862 ± 0.85109
    5.7928 ± 0.9503
    6.2221 ± 0.88162
        Week 3 (n=69,74,69)
    -0.9 ± 1.01
    -0.8 ± 1.13
    -1.1 ± 1.02
        Week 5 (n=71,71,67)
    -1.4 ± 1.17
    -1.4 ± 1.06
    -1.6 ± 1.2
        Week 9 (n=68,73,70)
    -1.7 ± 1.29
    -1.8 ± 1.3
    -2.1 ± 1.37
        Week 13 (n=67,72,67)
    -2 ± 1.43
    -2.1 ± 1.33
    -2.3 ± 1.34
        Week 17 (n=66,71,67)
    -2 ± 1.32
    -2.1 ± 1.39
    -2.4 ± 1.35
        Week 21 (n=60,65,59)
    -2 ± 1.28
    -1.9 ± 1.33
    -2.6 ± 1.35
        Week 25 (EOT; n=50,58,55)
    -1.7 ± 1.25
    -2 ± 1.3
    -2.5 ± 1.3
    No statistical analyses for this end point

    Secondary: % Change from Baseline in DAS28-CRP by Visit

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    End point title
    		 % Change from Baseline in DAS28-CRP by Visit
    End point description
    DAS28-CRP was calculated from the swollen joint count and tender joint count using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-CRP ≤3.2 implied low disease activity, DAS28-CRP >3.2 to ≤5.1 implied moderate to high disease activity, and DAS28-CRP <2.6 implied remission. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: % change from baseline
    arithmetic mean (standard deviation)
        Week 3 (n= 69, 74, 69)
    -16.1 ± 19.08
    -13.6 ± 20.41
    -18.6 ± 17.63
        Week 5 (n= 71, 71, 67)
    -25.4 ± 20.74
    -24 ± 18.22
    -26 ± 21.88
        Week 9 (n= 68, 73, 70)
    -31.2 ± 22.31
    -31 ± 21.92
    -34.2 ± 22.97
        Week 13 (n= 67, 72, 67)
    -34.7 ± 24
    -36.9 ± 22.1
    -37.4 ± 21.42
        Week 17 (n= 66, 71, 67)
    -34.9 ± 22.65
    -35.4 ± 23.28
    -39.1 ± 21.35
        Week 21 (n= 60, 65, 59)
    -35.5 ± 21.99
    -33.4 ± 22.56
    43.2 ± 21.39
        Week 25 EOT (n= 50, 58, 55)
    -31.1 ± 22.72
    -34.6 ± 22.25
    -40 ± 20.55
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Good European League Against Rheumatism (EULAR) Response Based on DAS28 by Visit

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    End point title
    		 Percentage of Participants with Good European League Against Rheumatism (EULAR) Response Based on DAS28 by Visit
    End point description
    The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 ≤3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to ≤5.1 or change from baseline >0.6 to ≤1.2 with DAS28 ≤5.1; non-responders: change from baseline ≤0.6, or change from baseline >0.6 and ≤1.2 with DAS28 >5.1. mITT population
    End point type
    Secondary
    End point timeframe
    Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: Percentage of participants
    number (not applicable)
        Week 3 (n= 69, 74, 69)
    14.5
    10.8
    8.7
        Week 5 (n=71, 71, 67)
    22.5
    22.5
    19.4
        Week 9 (n= 68, 73, 70)
    30.9
    31.5
    25.7
        Week 13 (n= 67, 72, 67)
    41.8
    44.4
    32.8
        Week 17 (n= 66, 71, 67)
    36.4
    38
    32.8
        Week 21 ( n= 60, 65, 59)
    35
    35.4
    47.5
        Week 25 EOT (n= 50, 58, 55)
    30
    36.2
    41.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Moderate EULAR Response Based on Disease Activity Score Based on DAS28 by Visit

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    End point title
    		 Percentage of Participants with Moderate EULAR Response Based on Disease Activity Score Based on DAS28 by Visit
    End point description
    The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 ≤3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to ≤5.1 or change from baseline >0.6 to ≤1.2 with DAS28 ≤5.1; non-responders: change from baseline ≤0.6, or change from baseline >0.6 and ≤1.2 with DAS28 >5.1. mITT population.
    End point type
    Secondary
    End point timeframe
    Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: % of participants
    number (not applicable)
        Week 3 (n= 69, 74, 69)
    33.3
    35.1
    42
        Week 5 (n= 71, 71, 67)
    47.9
    39.4
    43.3
        Week 9 (n= 68, 73, 70)
    45.6
    43.8
    54.3
        Week 13 (n= 67, 72, 67)
    38.8
    37.5
    44.8
        Week 17 (n= 66, 71, 67)
    45.5
    39.4
    53.7
        Week 21 (n= 60, 65, 59)
    51.7
    46.2
    39
        Week 25 EOT (n= 50, 58, 55)
    50
    46.6
    43.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants with No EULAR Response Based on DAS28 by Visit

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    End point title
    		 Percentage of Participants with No EULAR Response Based on DAS28 by Visit
    End point description
    The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 ≤3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to ≤5.1 or change from baseline >0.6 to ≤1.2 with DAS28 ≤5.1; non-responders: change from baseline ≤0.6, or change from baseline >0.6 and ≤1.2 with DAS28 >5.1. mITT population.
    End point type
    Secondary
    End point timeframe
    Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: % of participants
    number (not applicable)
        Week 3 (n= 69, 74, 69)
    52.2
    54.1
    49.3
        Week 5 (n= 71, 71, 67)
    29.6
    38
    37.3
        Week 9 (n= 68, 73, 70)
    23.5
    24.7
    20
        Week 13 (n= 67, 72, 67)
    19.4
    18.1
    22.4
        Week 17 (n= 66, 71, 67)
    18.2
    22.5
    13.4
        Week 21 (n= 60, 65, 59)
    13.3
    18.5
    13.6
        Week 25 EOT (n= 50, 58, 55)
    20
    17.2
    14.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Low Disease Activity Score (DAS; ≤3.2) by Visit

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    End point title
    		 Percentage of Participants with Low Disease Activity Score (DAS; ≤3.2) by Visit
    End point description
    DAS28-CRP was calculated from the swollen joint count and tender joint count using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-CRP ≤3.2 implied low disease activity. mITT population.
    End point type
    Secondary
    End point timeframe
    Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: % of participants
    number (not applicable)
        Week 3 (n=69,74,69)
    14.5
    10.8
    10.1
        Week 5 (n=71,71,67)
    23.9
    25.4
    19.4
        Week 9 (68,73,70)
    30.9
    32.9
    25.7
        Week 13 (n=67,72,67)
    41.8
    44.4
    32.8
        Week 17 (n=66,71,67)
    36.4
    38
    32.8
        Week 21 (n=60,65,59)
    35
    36.9
    47.5
        Week 25 (EOT; n=50,58,55)
    32
    37.9
    41.8
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 3
    Comparison groups
    Rituximab-Pfizer v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 1.78
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 3
    Comparison groups
    Rituximab-US v Rituximab-Pfizer
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 1.73
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 3
    Comparison groups
    Rituximab-EU v Rituximab-US
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 2.45
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 5
    Comparison groups
    Rituximab-Pfizer v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.88
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 5
    Comparison groups
    Rituximab-US v Rituximab-Pfizer
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.54
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 5
    Comparison groups
    Rituximab-US v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.44
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 9
    Comparison groups
    Rituximab-EU v Rituximab-Pfizer
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.73
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 9
    Comparison groups
    Rituximab-US v Rituximab-Pfizer
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.42
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 9
    Comparison groups
    Rituximab-US v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.31
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 13
    Comparison groups
    Rituximab-EU v Rituximab-Pfizer
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.56
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 13
    Comparison groups
    Rituximab-US v Rituximab-Pfizer
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.22
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 13
    Comparison groups
    Rituximab-EU v Rituximab-US
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.13
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 17
    Comparison groups
    Rituximab-EU v Rituximab-Pfizer
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.62
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 17
    Comparison groups
    Rituximab-US v Rituximab-Pfizer
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.44
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 17
    Comparison groups
    Rituximab-US v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.36
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 21
    Comparison groups
    Rituximab-EU v Rituximab-Pfizer
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.69
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 21
    Comparison groups
    Rituximab-US v Rituximab-Pfizer
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 2.1
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 21
    Comparison groups
    Rituximab-US v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.95
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 25
    Comparison groups
    Rituximab-Pfizer v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 2
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 25
    Comparison groups
    Rituximab-US v Rituximab-Pfizer
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 2.18
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 25
    Comparison groups
    Rituximab-US v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.73

    Secondary: Percentage of Participants with DAS Remission (DAS <2.6) by Visit

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    End point title
    		 Percentage of Participants with DAS Remission (DAS <2.6) by Visit
    End point description
    DAS28-CRP was calculated from the swollen joint count and tender joint count using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-CRP <2.6 implied remission. mITT population.
    End point type
    Secondary
    End point timeframe
    Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: Percentage of Participants
    number (not applicable)
        Week 3 (n=69,74,69)
    8.7
    4.1
    7.2
        Week 5 (n=71,71,67)
    16.9
    8.5
    11.9
        Week 9 (n=68,73,70)
    26.5
    20.5
    20
        Week 13 (n=67,72,67)
    28.4
    29.2
    25.4
        Week 17 (n=66,71,67)
    25.8
    25.4
    23.9
        Week 21 (n=60,65,59)
    25
    16.9
    30.5
        Week 25 (EOT; n=50,58,55)
    28
    24.1
    23.6
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 3
    Comparison groups
    Rituximab-Pfizer v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 1.79
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 3
    Comparison groups
    Rituximab-US v Rituximab-Pfizer
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 2.6
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 3
    Comparison groups
    Rituximab-EU v Rituximab-US
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 7.2
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 5
    Comparison groups
    Rituximab-EU v Rituximab-Pfizer
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 1.26
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 5
    Comparison groups
    Rituximab-Pfizer v Rituximab-US
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Log risk ratio
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 1.62
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 5
    Comparison groups
    Rituximab-EU v Rituximab-US
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 3.86
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 9
    Comparison groups
    Rituximab-EU v Rituximab-Pfizer
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.41
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 9
    Comparison groups
    Rituximab-US v Rituximab-Pfizer
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.4
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 9
    Comparison groups
    Rituximab-EU v Rituximab-US
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.87
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 13
    Comparison groups
    Rituximab-EU v Rituximab-Pfizer
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.74
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 13
    Comparison groups
    Rituximab-US v Rituximab-Pfizer
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.57
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 13
    Comparison groups
    Rituximab-US v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.5
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 17
    Comparison groups
    Rituximab-Pfizer v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.74
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 17
    Comparison groups
    Rituximab-US v Rituximab-Pfizer
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.68
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 17
    Comparison groups
    Rituximab-US v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.69
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 21
    Comparison groups
    Rituximab-EU v Rituximab-Pfizer
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.36
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 21
    Comparison groups
    Rituximab-Pfizer v Rituximab-US
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 2.19
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 21
    Comparison groups
    Rituximab-EU v Rituximab-US
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 3.5
    Statistical analysis title
    		 Rituximab-EU versus rituximab-Pfizer at Week 25
    Comparison groups
    Rituximab-Pfizer v Rituximab-EU
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.63
    Statistical analysis title
    		 Rituximab-US versus rituximab-Pfizer at Week 25
    Comparison groups
    Rituximab-Pfizer v Rituximab-US
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.62
    Statistical analysis title
    		 Rituximab-US versus rituximab-EU at Week 25
    Comparison groups
    Rituximab-EU v Rituximab-US
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Log risk ratio
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.89

    Secondary: Baseline and Change from Baseline in HAQ-DI by Visit

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    End point title
    		 Baseline and Change from Baseline in HAQ-DI by Visit
    End point description
    Health Assessment Questionnaire - Disability Index (HAQ-DI): participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    73
    74
    73
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Baseline (n=73,74,73)
    1.6541 ± 0.5734
    1.5929 ± 0.53597
    1.7466 ± 0.62081
        Week 3 (n=70,74,70)
    -0.2 ± 0.39
    -0.2 ± 0.34
    -0.2 ± 0.33
        Week 5 (n=72,70,68)
    -0.3 ± 0.39
    -0.3 ± 0.45
    -0.3 ± 0.43
        Week 9 (n=68,73,70)
    -0.4 ± 0.47
    -0.5 ± 0.5
    -0.5 ± 0.54
        Week 13 (n=67,72,68)
    -0.4 ± 0.55
    -0.6 ± 0.56
    -0.5 ± 0.52
        Week 17 (n=66,71,67)
    -0.3 ± 0.49
    -0.6 ± 0.58
    -0.5 ± 0.55
        Week 21 (n=63,70,64)
    -0.4 ± 0.53
    -0.6 ± 0.58
    -0.6 ± 0.61
        Week 25 (EOT; n=52,59,55)
    -0.4 ± 0.49
    -0.5 ± 0.63
    -0.6 ± 0.57
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in HAQ-DI Score by Visit

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    End point title
    		 Percent Change from Baseline in HAQ-DI Score by Visit
    End point description
    HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
    End point values
    		 Rituximab-Pfizer Rituximab-EU Rituximab-US
    Number of subjects analysed
    72
    74
    73
    Units: Percentage change
    arithmetic mean (standard deviation)
        Week 3 (n=70,74,70)
    -10.4 ± 37.27
    -13.2 ± 26.03
    -9 ± 25.68
        Week 5 (n=72,70,68)
    -15.1 ± 40
    -23.5 ± 30.45
    -14.8 ± 43.82
        Week 9 (n=68,73,70)
    -22.4 ± 35.96
    -31.7 ± 34.64
    -24.5 ± 35.51
        Week 13 (n=67,72,68)
    -14.6 ± 50.35
    -39.5 ± 37.46
    -30.7 ± 31.91
        Week 17 (n=66,71,67)
    -16.9 ± 48.95
    -39.1 ± 38.85
    -28.8 ± 36.43
        Week 21 (n=63,70,64)
    -21 ± 48.04
    -39.2 ± 38.34
    -33.5 ± 35.18
        Week 25 (EOT; n=52,59,55)
    -17.7 ± 54.01
    -37.1 ± 41.18
    -38.4 ± 34.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected for 28 days after the last administration of study drug or, in the case of incomplete B-cell count recovery, for up to 1 year after Study Day 1.
    Adverse event reporting additional description
    The same event may appear as both an AE and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Rituximab-Pfizer
    Reporting group description
    		 Rituximab-Pfizer group received intravenous (IV) rituximab (PF-05280586) infusion 1000 milligrams (mg) per (/) 500 milliliters (mL) (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.

    Reporting group title
    Rituximab-US
    Reporting group description
    		 Rituximab-US group received IV rituximab (Rituxan) infusion 1000 mg/500 mL (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.

    Reporting group title
    Rituximab-EU
    Reporting group description
    		 Rituximab-EU group received IV rituximab (MabThera) infusion 1000 mg/500 mL (preceded by 100 mg methylprednisolone, an antipyretic such as paracetamol, and an antihistamine such as diphenhydramine) on Study Days 1 and 15 and continued to receive a stable background regimen of MTX 10 to 25 mg/week (7.5 mg/week in the event of prior poor tolerance) for up to 25 weeks. Folate supplementation was encouraged according to local standard of care.

    Serious adverse events
    		 Rituximab-Pfizer Rituximab-US Rituximab-EU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 73 (6.85%)
    4 / 73 (5.48%)
    2 / 74 (2.70%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bone neoplasm
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenic purpura
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Intentional self-injury
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Rituximab-Pfizer Rituximab-US Rituximab-EU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 73 (68.49%)
    45 / 73 (61.64%)
    40 / 74 (54.05%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Skin papilloma
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    2
    Hot flush
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    1
    Hypertension
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 73 (1.37%)
    2 / 74 (2.70%)
         occurrences all number
    4
    1
    2
    Hypotension
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Venous insufficiency
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Asthenia
         subjects affected / exposed
    3 / 73 (4.11%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    3
    0
    0
    Chest discomfort
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    1
    0
    1
    Fatigue
         subjects affected / exposed
    5 / 73 (6.85%)
    1 / 73 (1.37%)
    1 / 74 (1.35%)
         occurrences all number
    7
    1
    2
    Inflammation
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Infusion site extravasation
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Local swelling
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    1
    0
    1
    Reproductive system and breast disorders
    Prostatomegaly
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Dry throat
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 73 (1.37%)
    3 / 73 (4.11%)
    0 / 74 (0.00%)
         occurrences all number
    1
    3
    0
    Hypoxia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    1
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    1
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Pulmonary congestion
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Rales
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 73 (2.74%)
    0 / 74 (0.00%)
         occurrences all number
    1
    2
    0
    Respiratory disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory tract congestion
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Sneezing
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Sputum discoloured
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Throat irritation
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 73 (2.74%)
    1 / 74 (1.35%)
         occurrences all number
    1
    2
    1
    Wheezing
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 73 (0.00%)
    3 / 73 (4.11%)
    1 / 74 (1.35%)
         occurrences all number
    0
    4
    1
    Depression
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 73 (4.11%)
    1 / 74 (1.35%)
         occurrences all number
    2
    3
    1
    Insomnia
         subjects affected / exposed
    1 / 73 (1.37%)
    3 / 73 (4.11%)
    2 / 74 (2.70%)
         occurrences all number
    1
    3
    2
    Mood swings
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Restlessness
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Investigations
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    1
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Blood calcium increased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    1
    1
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Blood pressure decreased
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    0
    0
    2
    Blood urea increased
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    1
    Haematocrit decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Liver function test abnormal
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    2
    1
    0
    Epicondylitis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 73 (2.74%)
    1 / 74 (1.35%)
         occurrences all number
    1
    2
    1
    Foot fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Fractured sacrum
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Hand fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Infusion related reaction
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Laceration
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    1
    0
    1
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle contusion
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Nail avulsion
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Tooth fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Underdose
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Vaccination complication
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Wound
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Atrial flutter
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    2
    0
    Extrasystoles
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Tachycardia paroxysmal
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 73 (2.74%)
    2 / 73 (2.74%)
    1 / 74 (1.35%)
         occurrences all number
    2
    2
    1
    Headache
         subjects affected / exposed
    3 / 73 (4.11%)
    4 / 73 (5.48%)
    2 / 74 (2.70%)
         occurrences all number
    5
    4
    2
    Hypoaesthesia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Lethargy
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    1
    0
    1
    Migraine
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    1
    1
    0
    Neuralgia
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Sciatica
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    0
    Sinus headache
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Ear disorder
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Ear pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Ear pruritus
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Vertigo positional
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Abnormal sensation in eye
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    2
    Blepharitis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    0
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Eye haemorrhage
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Eye pruritus
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Eyelid pain
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    0 / 74 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal pain
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    0 / 74 (0.00%)
         occurrences all number
    0
    3
    0
    Abdominal pain lower
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Abdominal tenderness
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Colitis ulcerative
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    2 / 74 (2.70%)
         occurrences all number
    1
    1
    2
    Diarrhoea
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 73 (2.74%)
    2 / 74 (2.70%)
         occurrences all number
    1
    3
    2
    Diverticulum
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Diverticulum intestinal
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    2
    0
    2
    Dyspepsia
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    2
    1
    0
    Dysphagia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    1
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    1
    Haematochezia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Lip swelling
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Lip ulceration
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 73 (1.37%)
    4 / 73 (5.48%)
    1 / 74 (1.35%)
         occurrences all number
    1
    5
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Tongue ulceration
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    2 / 74 (2.70%)
         occurrences all number
    0
    2
    2
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Campbell de Morgan spots
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Eczema
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Intertrigo
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Onycholysis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    3 / 73 (4.11%)
    2 / 73 (2.74%)
    1 / 74 (1.35%)
         occurrences all number
    3
    2
    1
    Rash
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    3
    0
    1
    Rash vesicular
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Skin lesion
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    1
    0
    1
    Skin mass
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Urticaria
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Hydronephrosis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Renal pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 73 (4.11%)
    4 / 73 (5.48%)
    4 / 74 (5.41%)
         occurrences all number
    3
    4
    5
    Arthritis
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    1
    1
    0
    Back pain
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 73 (2.74%)
    1 / 74 (1.35%)
         occurrences all number
    1
    2
    1
    Bursitis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Costochondritis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Fibromyalgia
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    1
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Joint instability
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Joint swelling
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    0
    Muscle atrophy
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    1
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 73 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    4
    0
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Osteonecrosis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    0 / 74 (0.00%)
         occurrences all number
    0
    2
    0
    Periarthritis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 73 (1.37%)
    5 / 73 (6.85%)
    5 / 74 (6.76%)
         occurrences all number
    1
    6
    8
    Spinal pain
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Spondylolisthesis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Synovitis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Arthritis infective
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    3 / 73 (4.11%)
    4 / 73 (5.48%)
    2 / 74 (2.70%)
         occurrences all number
    3
    4
    2
    Cellulitis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Ear infection
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    1
    0
    1
    Furuncle
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    2 / 74 (2.70%)
         occurrences all number
    0
    2
    2
    Gastroenteritis viral
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    1
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Herpes simplex
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Infected bites
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    2
    0
    Influenza
         subjects affected / exposed
    2 / 73 (2.74%)
    2 / 73 (2.74%)
    1 / 74 (1.35%)
         occurrences all number
    2
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 73 (4.11%)
    3 / 73 (4.11%)
    1 / 74 (1.35%)
         occurrences all number
    3
    3
    1
    Oral herpes
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Otitis externa
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    1
    0
    1
    Sinusitis
         subjects affected / exposed
    3 / 73 (4.11%)
    2 / 73 (2.74%)
    6 / 74 (8.11%)
         occurrences all number
    3
    2
    8
    Tooth abscess
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    1
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 73 (9.59%)
    4 / 73 (5.48%)
    5 / 74 (6.76%)
         occurrences all number
    7
    4
    6
    Urinary tract infection
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 73 (2.74%)
    0 / 74 (0.00%)
         occurrences all number
    2
    2
    0
    Viral infection
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    4
    0
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jan 2012
    The original protocol (dated 15 December 2011) was amended on 12 January 2012 with administrative changes. The purpose of this amendment was to correct typographical errors in the Schedule of Activities, References, and Appendices 6 and 7. Appendix 6 (Rescue Therapy) was removed to prevent confusion.
    20 Jan 2012
    The protocol was amended on 20 January 2012 with administrative changes. The purpose of this amendment was to adjust terminology referencing biosimilarity and reference products per advice from US Food and Drug Administration (FDA).
    02 Feb 2012
    The protocol was amended on 02 February 2012 with administrative changes. The purpose of this amendment was to adjust terminology referencing product licensure per advice from US FDA.
    07 Sep 2012
    The protocol was amended on 07 September 2012 with administrative changes, including corrections to typographical errors and updates to section numbering along with clarifications/ corrections to the following sections of the protocol: Primary PK parameters, Schedule of Activities, PK/PD Study Sampling Time Points, Safety of Rituximab (Section 1.1.1.2), Rationale, PK Evaluations, Inclusion and Exclusion Criteria, Preparation and Dosing, Stable Background Pain or Other Arthritis Therapy, Pharmacokinetic Evaluation, Pharmacodynamic Evaluation, Per Protocol (PP) Population, Pharmacokinetic Analysis, Analysis of Clinical Response Endpoints, Interim Look, Concomitant Medications and Procedures.
    22 Aug 2013
    The protocol was amended on 22 August 2013 with administrative changes, including corrections to typographical errors and updates to section numbering. Population PK/PD modelling was added as a secondary objective. Visit windows were clarified and inconsistencies within the protocol were corrected. It was clarified that tuberculosis screening should have been conducted per local guidelines and alternative radiological techniques to chest x-ray were acceptable. Updated language regarding interim PK assessment. Corrected dose to 1000 mg, rather than 1000 mg/kg. Updated sections regarding the timeframe for reporting AEs, occupational exposure, exposure during pregnancy, and communication of results to conform to current sponsor standard language.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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