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    Clinical Trial Results:
    A Randomised, open labelled study in anti-TNFa inadequate responders to investigate the mechanisms for Response - Resistance to Rituximab versus Tocilizumab in RA (R4-RA)

    Summary
    EudraCT number
    		 2012-002535-28
    Trial protocol
    		 GB   PT   BE   IT   ES   NL  
    Global end of trial date
    11 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jul 2020
    First version publication date
    05 Jul 2020
    Other versions
    Summary report(s)
    		 SAEs occuring after treatment phase of study

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    R4-RA
    Additional study identifiers
    ISRCTN number
    		 ISRCTN97443826
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    Joint Research Management Office QM Innovation Building, 5 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    Professor Costantino Pitzalis, Centre for Experimental Medicine and Rheumatology, Queen Mary University of London, emrclinicaltrials@qmul.ac.uk
    Scientific contact
    Professor Costantino Pitzalis, Centre for Experimental Medicine and Rheumatology, Queen Mary University of London, c.pitzalis@qmul.ac.uk
    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
    05 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main aim of this project is to test the hypothesis that the presence or absence of specific synovial cellular and molecular signatures(B cells and B cell-associated signatures), assessed following a synovial tissue biopsy, will enrich for response / non-response to the B cell depleting anti-CD20 monoclonal antibody (mAb) Rituximab. The primary aim of this project is to show that in patients failing anti-TNF therapy, with a B cell poor synovial pathotype, Rituximab is inferior to Tocilizumab therapy.
    Protection of trial subjects
    Both IMPs being used in this trial are approved for use in this patient population. Infusions of Rituximab may be associated with infusion reactions of varying severity in up to 15% of patients. Most are mild and managed by slowing the rate of the Rituximab infusion. Occasionally, more severe reactions necessitate stopping the infusion and rarely, anaphylaxis has been reported. Patients will be given corticosteroids (methylprednisolone 100mg intravenous), antihistamines (chlorphenamine 10mg intravenous) and paracetamol (1000mg orally) before the infusion to minimise the risk of reactions. The risk of infection will be discussed with the patient prior to enrolment in the study however patients would be at no greater risk than routine care within the NHS. Infusion reactions with Tocilizumab are rare. Occasionally patients may experience chills or fevers but these are self-limiting or rarely requiring paracetamol. The risk of infection will be discussed with the patient prior to enrolment in the study however patients would be at no greater risk than routine care within the NHS. Ultrasound-guided synovial biopsy is a quick, safe and well tolerated procedure; patients who consent to the study and therefore synovial biopsy will have a longer appointment in hospital and may have discomfort from the local anaesthetic and biopsy procedure however audit data of this procedure confirms that it is well tolerated and patients are agreeable to multiple biopsies. The risks of venepuncture may include fainting, pain and/or bruising at the site of the needle puncture. Every possible effort will be taken to minimise the potential of these risks occurring.
    Background therapy
    		 Only entry into the trial patients should be receiving a stable dose Methotrexate for at least 4 weeks prior to biopsy visit.
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    28 Feb 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 109
    Country: Number of subjects enrolled
    Belgium: 26
    Country: Number of subjects enrolled
    Italy: 14
    Worldwide total number of subjects
    164
    EEA total number of subjects
    164
    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)
    120
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were recruited from rheumatology clinics across 19 sites in the United Kingdom, Italy, Belgium, Portugal and Spain. Recruitment began in February 2013 and ended in November 2017.

    Pre-assignment
    Screening details
    		 212 patients were approached to join the study, and 190 of these went on to consent to participation in the trial. 26 of these did not continue to randomization, 13 did not meet the inclusion criteria following the screening visit, 6 declined further participation (3 due to the biopsy), and 7 for other reasons not recorded.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 Patients randomized to rituximab who received at least one dose of IMP
    Arm type
    		 Active drug

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab is available as 50ml single-use vials containing 500mg Rituximab for infusion (10mg/ml). Patients randomised to Rituximab will have an infusion cycle at baseline consisting of two infusions given 2 weeks apart (Day 0 and Day 15). A patient initially randomised to Rituximab, deemed a responder at 16 weeks (CDAI ≥50% improvement from baseline assessment) who continues to have active disease (CDAI ≥10.1) or flares (CDAI ≥10.1) will be re-treated at 24 weeks, as per the SmPC. Rituximab was prescribed according as per license and thus was sourced from local clinical supplies at each trial site.

    Arm title
    		 Tocilizumab
    Arm description
    		 Patients randomized to tocilizumab who received at least one dose of IMP
    Arm type
    		 Active drug

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tocilizumab is available in 20mg/ml vials in a concentrate for intravenous infusion. Tocilizumab was prescribed according as per license and thus was sourced from local clinical supplies at each trial site. Infusions were given every 4 weeks starting at baseline with the last infusion given at 44 weeks.

    Number of subjects in period 1 [1]
    		Rituximab Tocilizumab
    Started
    82
    79
    Completed
    82
    79
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 212 patients were approached to join the study, and 190 of these went on to consent to participation in the trial. 26 of these did not continue to randomization, 13 did not meet the inclusion criteria following the screening visit, 6 declined further participation (3 due to the biopsy), and 7 for other reasons not recorded.
    Period 2
    Period 2 title
    Baseline to Week 16
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 -
    Arm type
    		 Active drug

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab is available as 50ml single-use vials containing 500mg Rituximab for infusion (10mg/ml). Patients randomised to Rituximab will have an infusion cycle at baseline consisting of two infusions given 2 weeks apart (Day 0 and Day 15). A patient initially randomised to Rituximab, deemed a responder at 16 weeks (CDAI ≥50% improvement from baseline assessment) who continues to have active disease (CDAI ≥10.1) or flares (CDAI ≥10.1) will be re-treated at 24 weeks, as per the SmPC. Rituximab was prescribed according as per license and thus was sourced from local clinical supplies at each trial site.

    Arm title
    		 Tocilizumab
    Arm description
    		 -
    Arm type
    		 Active drug

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tocilizumab is available in 20mg/ml vials in a concentrate for intravenous infusion. Tocilizumab was prescribed according as per license and thus was sourced from local clinical supplies at each trial site. Infusions were given every 4 weeks starting at baseline with the last infusion given at 44 weeks.

    Number of subjects in period 2
    		Rituximab Tocilizumab
    Started
    82
    79
    Completed
    81
    73
    Not completed
    1
    6
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    1
    5
    Period 3
    Period 3 title
    Week 16 to Week 48
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 Patients who were randomized to rituximab and did not switch treatment for the duration of the trial.
    Arm type
    		 Active drug

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab is available as 50ml single-use vials containing 500mg Rituximab for infusion (10mg/ml). Patients randomised to Rituximab will have an infusion cycle at baseline consisting of two infusions given 2 weeks apart (Day 0 and Day 15). A patient initially randomised to Rituximab, deemed a responder at 16 weeks (CDAI ≥50% improvement from baseline assessment) who continues to have active disease (CDAI ≥10.1) or flares (CDAI ≥10.1) will be re-treated at 24 weeks, as per the SmPC. Rituximab was prescribed according as per license and thus was sourced from local clinical supplies at each trial site.

    Arm title
    		 Tocilizumab
    Arm description
    		 Patients who were randomized to tocilizumab and did not switch treatment for the duration of the trial.
    Arm type
    		 Active drug

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tocilizumab is available in 20mg/ml vials in a concentrate for intravenous infusion. Tocilizumab was prescribed according as per license and thus was sourced from local clinical supplies at each trial site. Infusions were given every 4 weeks starting at baseline with the last infusion given at 44 weeks.

    Arm title
    		 Rituximab+Tocilizumab
    Arm description
    		 Patients who were randomized to rituximab but switched to tocilizumab at week 16 or later.
    Arm type
    		 Active drug

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab is available as 50ml single-use vials containing 500mg Rituximab for infusion (10mg/ml). Patients randomised to Rituximab will have an infusion cycle at baseline consisting of two infusions given 2 weeks apart (Day 0 and Day 15). A patient initially randomised to Rituximab, deemed a responder at 16 weeks (CDAI ≥50% improvement from baseline assessment) who continues to have active disease (CDAI ≥10.1) or flares (CDAI ≥10.1) will be re-treated at 24 weeks, as per the SmPC. Rituximab was prescribed according as per license and thus was sourced from local clinical supplies at each trial site.

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tocilizumab is available in 20mg/ml vials in a concentrate for intravenous infusion. Tocilizumab was prescribed according as per license and thus was sourced from local clinical supplies at each trial site. Infusions were given every 4 weeks starting at baseline with the last infusion given at 44 weeks.

    Arm title
    		 Tocilizumab+Rituximab
    Arm description
    		 Patients who were randomized to tocilizumab and were switched to rituximab at week 16 or later
    Arm type
    		 Active drug

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tocilizumab is available in 20mg/ml vials in a concentrate for intravenous infusion. Tocilizumab was prescribed according as per license and thus was sourced from local clinical supplies at each trial site. Infusions were given every 4 weeks starting at baseline with the last infusion given at 44 weeks.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab is available as 50ml single-use vials containing 500mg Rituximab for infusion (10mg/ml). Patients randomised to Rituximab will have an infusion cycle at baseline consisting of two infusions given 2 weeks apart (Day 0 and Day 15). A patient initially randomised to Rituximab, deemed a responder at 16 weeks (CDAI ≥50% improvement from baseline assessment) who continues to have active disease (CDAI ≥10.1) or flares (CDAI ≥10.1) will be re-treated at 24 weeks, as per the SmPC. Rituximab was prescribed according as per license and thus was sourced from local clinical supplies at each trial site.

    Number of subjects in period 3
    		Rituximab Tocilizumab Rituximab+Tocilizumab Tocilizumab+Rituximab
    Started
    55
    58
    26
    15
    Completed
    41
    42
    35
    18
    Not completed
    14
    16
    3
    8
         Adverse event, serious fatal
    1
    -
    -
    -
         Consent withdrawn by subject
    1
    2
    2
    3
         Adverse event, non-fatal
    -
    -
    -
    4
         Transferred to other arm/group
    12
    11
    -
    -
         Pregnancy
    -
    1
    -
    -
         Intermittent Illness
    -
    2
    1
    -
         Lost to follow-up
    -
    -
    -
    1
    Joined
    0
    0
    12
    11
         Transferred in from other group/arm
    -
    -
    12
    11

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Patients randomized to rituximab who received at least one dose of IMP

    Reporting group title
    Tocilizumab
    Reporting group description
    		 Patients randomized to tocilizumab who received at least one dose of IMP

    Reporting group values
    		 Rituximab Tocilizumab Total
    Number of subjects
    		 82 79 161
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 61 59 120
        From 65-84 years
    		 21 20 41
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 55.72 (47.67 to 65.54) 55.50 (47.36 to 65.07) -
    Gender categorical
    Units: Subjects
        Female
    		 62 66 128
        Male
    		 20 13 33
    Pathotype
    Patients were assigned a histological classification based on their baseline synovial biopsy (B-cell poor, B-cell rich, Germinal centre or unknown)
    Units: Subjects
        B-cell poor
    		 38 41 79
        B-cell rich
    		 33 31 64
        Germinal centre
    		 5 4 9
        Unknown
    		 6 3 9
    Rheumatoid factor (RF) OR Anti–citrullinated protein antibody (ACPA) positive
    Units: Subjects
        Positive
    		 70 62 132
        Negative
    		 12 17 29
    Rheumatoid factor (RF) positive
    Units: Subjects
        Positive
    		 58 47 105
        Negative
    		 24 32 56
    Anti–citrullinated protein antibody (ACPA) positive
    Units: Subjects
        Positive
    		 63 56 119
        Negative
    		 19 23 42
    Previous Methotrexate use
    Units: Subjects
        Yes
    		 82 79 161
        No
    		 0 0 0
    Number of previous biologics used, [anti-TNF/Other**]
    Units: Subjects
        One
    		 62 54 116
        Two
    		 14 22 36
        Three or more
    		 6 3 9
    Number of concomitant DMARDs
    Units: Subjects
        Zero
    		 42 43 85
        One
    		 14 17 31
        Two
    		 20 12 32
        Three or more
    		 6 7 13
    Previous Prednisolone Use
    Units: Subjects
        Yes
    		 44 46 90
        No
    		 38 33 71
    Disease Duration
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 9.50 (4.00 to 20.75) 9.00 (4.00 to 18.00) -
    Clinical disease activity index (CDAI)
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 30.65 (22.80 to 40.58) 29.40 (21.50 to 40.30) -
    Erythrocyte sedimentation rate (ESR)
    Units: mm/h
        median (inter-quartile range (Q1-Q3))
    		 34.00 (16.50 to 50.00) 28.00 (18.00 to 48.00) -
    C-reactive protein (CRP)
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    		 10.00 (5.00 to 23.00) 15.10 (6.00 to 32.50) -
    Haemoglobin, g/L
    Units: g/L
        median (inter-quartile range (Q1-Q3))
    		 121.00 (109.00 to 131.00) 123.00 (111.50 to 131.75) -
    Number of tender joints, 0-28
    Units: Score 0-28
        median (inter-quartile range (Q1-Q3))
    		 10.50 (6.25 to 18.75) 11.00 (6.00 to 16.00) -
    Number of swollen joints, 0-28
    Units: Score 0-28
        median (inter-quartile range (Q1-Q3))
    		 6.00 (4.00 to 9.00) 6.00 (3.00 to 10.50) -
    28 joint count Disease Activity Score (DAS-28), ESR
    Units: Score
        arithmetic mean (standard deviation)
    		 5.84 ± 1.19 5.78 ± 1.31 -
    28 joint count Disease Activity Score (DAS-28), CRP
    Units: Score
        arithmetic mean (standard deviation)
    		 5.30 ± 1.15 5.33 ± 1.26 -
    Ultrasound 12-max score (Power Doppler)
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 4.00 (0.25 to 8.00) 6.00 (1.50 to 10.00) -
    Ultrasound 12-max score (Synovial Thickening)
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 16.00 (13.00 to 22.00) 15.00 (10.00 to 20.25) -
    van der Heijde modified Sharp score (SHSS), Total
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 30.00 (11.00 to 70.00) 24.00 (9.00 to 53.00) -
    van der Heijde modified Sharp score (SHSS), Joint Space Narrowing
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 15.00 (4.00 to 50.00) 16.00 (2.00 to 39.00) -
    n der Heijde modified Sharp score (SHSS), Erosion
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 10.00 (6.00 to 23.00) 10.00 (3.00 to 22.00) -
    Creatinine (μmol/L)
    Units: μmol/L
        median (inter-quartile range (Q1-Q3))
    		 63.00 (53.00 to 73.00) 59.50 (54.00 to 67.75) -
    Alanine aminotransferase (ALT), U/L
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    		 16.00 (12.00 to 21.00) 16.00 (12.00 to 23.00) -
    Aspartate aminotransferase (AST), U/L
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    		 19.00 (15.00 to 22.00) 18.00 (16.00 to 22.00) -
    Haemoglobin, g/L
    Units: g/L
        median (inter-quartile range (Q1-Q3))
    		 121.00 (109.00 to 131.00) 123.00 (111.50 to 131.75) -
    White Blood Cell count, 10^9/L
    Units: 10^9/L
        median (inter-quartile range (Q1-Q3))
    		 8.00 (6.60 to 10.20) 8.45 (7.00 to 10.47) -
    Platelets, 10^9/L
    Units: 10^9/L
        median (inter-quartile range (Q1-Q3))
    		 302.00 (256.00 to 344.00) 304.00 (251.75 to 394.50) -
    Neutrophils, 10^9/L
    Units: 10^9/L
        median (inter-quartile range (Q1-Q3))
    		 5.70 (4.20 to 7.30) 5.60 (4.62 to 7.11) -
    Lymphocytes, 10^9/L
    Units: 10^9/L
        median (inter-quartile range (Q1-Q3))
    		 1.70 (1.20 to 2.30) 1.80 (1.40 to 2.40) -
    Patient’s global assessment—arthritis,0–100 VAS
    Patient’s global assessment—arthritis,0–100 Visual Analogue Score (VAS)
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 71.00 (50.25 to 82.00) 74.00 (51.50 to 87.50) -
    Physician’s global assessment, 0–100 VAS
    Physician’s global assessment, 0–100 Visual Analogue Score (VAS)
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 60.00 (49.00 to 79.75) 64.00 (46.00 to 76.50) -
    Patient’s assessment of early morning stiffness, 0–100 VAS
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 35.00 (20.00 to 100.00) 60.00 (20.00 to 100.00) -
    Patient’s assessment of tiredness, 0–100 VAS
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 67.00 (44.50 to 78.75) 70.00 (50.00 to 86.50) -
    Patient’s assessment of pain, 0–100 VAS
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 66.50 (48.25 to 83.50) 72.00 (43.00 to 87.00) -
    HAQ total score
    Health assessment questionnaire (HAQ)
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 1.75 (1.25 to 2.13) 1.75 (1.25 to 2.13) -
    Functional Assessment of Chronic Illness Therapy (FACIT) score
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 23.00 (15.00 to 32.00) 21.00 (13.00 to 33.75) -
    Short form-36,Physical functioning, 0-100
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 30.00 (10.00 to 48.75) 30.00 (15.00 to 45.00) -
    Short form-36, Physical role functioning, 0-100
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 0.00 (0.00 to 25.00) 0.00 (0.00 to 0.00) -
    Short form-36, Emotional role functioning, 0-100
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 33.33 (0.00 to 91.67) 0.00 (0.00 to 66.67) -
    Short form-36, Vitality, 0-100
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 35.00 (20.00 to 50.00) 30.00 (20.00 to 45.00) -
    Short form-36, Mental health, 0-100
    Units: score
        arithmetic mean (standard deviation)
    		 61.22 ± 19.08 58.73 ± 20.66 -
    Short form-36, Social role functioning, 0-100
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 37.50 (25.00 to 62.50) 50.00 (25.00 to 75.00) -
    Short form-36, Bodily pain, 0-100
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 22.50 (22.50 to 45.00) 22.50 (10.00 to 45.00) -
    Short form-36, General health perceptions, 0-100
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 35.00 (25.00 to 45.00) 35.00 (25.00 to 50.00) -

    End points

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    End points reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Patients randomized to rituximab who received at least one dose of IMP

    Reporting group title
    Tocilizumab
    Reporting group description
    		 Patients randomized to tocilizumab who received at least one dose of IMP
    Reporting group title
    Rituximab
    Reporting group description
    		 -

    Reporting group title
    Tocilizumab
    Reporting group description
    		 -
    Reporting group title
    Rituximab
    Reporting group description
    		 Patients who were randomized to rituximab and did not switch treatment for the duration of the trial.

    Reporting group title
    Tocilizumab
    Reporting group description
    		 Patients who were randomized to tocilizumab and did not switch treatment for the duration of the trial.

    Reporting group title
    Rituximab+Tocilizumab
    Reporting group description
    		 Patients who were randomized to rituximab but switched to tocilizumab at week 16 or later.

    Reporting group title
    Tocilizumab+Rituximab
    Reporting group description
    		 Patients who were randomized to tocilizumab and were switched to rituximab at week 16 or later

    Subject analysis set title
    SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis set

    Subject analysis set title
    ITT week 16 - B cell poor Rituximab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subgroup of patients classified as B cell poor by histology classification and analysed as ITT at week 16

    Subject analysis set title
    ITT week 16 - B cell poor Tocilizumab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subgroup of patients classified as B cell poor by histology classification and analysed as ITT at week 16

    Subject analysis set title
    ITT week 16 - B cell rich Rituximab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subgroup of patients classified as B cell rich by histology classification and analysed as ITT at week 16

    Subject analysis set title
    ITT week 16 - B cell rich Tocilizumab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subgroup of patients classified as B cell rich by histology classification and analysed as ITT at week 16

    Subject analysis set title
    ITT week 16 - B cell poor (RNA_seq) Rituximab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subgroup of patients classified as B cell poor by RNA-seq classification and analysed as ITT at week 16

    Subject analysis set title
    ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subgroup of patients classified as B cell poor by RNA-sequencing classification and analysed as ITT at week 16

    Subject analysis set title
    ITT week 16 - B cell rich (RNA_seq) Rituximab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subgroup of patients classified as B cell rich by RNA-sequencing classification and analysed as ITT at week 16

    Subject analysis set title
    ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subgroup of patients classified as B cell rich by RNA-sequencing classification and analysed as ITT at week 16

    Subject analysis set title
    PP week 16 - B cell poor Rituximab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell poor by histology classification and analysed as PP at week 16

    Subject analysis set title
    PP week 16 - B cell poor Tocilizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell poor by histology classification and analysed as PP at week 16

    Subject analysis set title
    PP week 16 - B cell rich Rituximab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell rich by histology classification and analysed as PP at week 16

    Subject analysis set title
    PP week 16 - B cell rich Tocilizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell rich by histology classification and analysed as PP at week 16

    Subject analysis set title
    PP week 16 - B cell poor (RNA_seq) Rituximab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell poor by RNA sequencing classification and analysed as PP at week 16

    Subject analysis set title
    PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell poor by RNA-sequencing classification and analysed as PP at week 16

    Subject analysis set title
    PP week 16 - B cell rich (RNA_seq) RItuximab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell rich by RNA-sequencing classification and analysed as PP at week 16

    Subject analysis set title
    PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell rich by RNA-sequencing classification and analysed as PP at week 16

    Subject analysis set title
    week 24 - B cell poor Rituximab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell poor by histology classification and analysed as PP at week 24

    Subject analysis set title
    week 24 - B cell poor Tocilizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell poor by histology classification and analysed as PP at week 24

    Subject analysis set title
    week 24 - B cell rich Rituximab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell rich by histology classification and analysed as PP at week 24

    Subject analysis set title
    week 24 - B cell rich Tocilizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell rich by histology classification and analysed as PP at week 24

    Subject analysis set title
    week 36 - B cell poor Rituximab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell poor by histology classification and analysed as PP at week 36

    Subject analysis set title
    week 36 - B cell poor Tocilizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell poor by histology classification and analysed as PP at week 36

    Subject analysis set title
    week 36 - B cell rich Rituximab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell rich by histology classification and analysed as PP at week 36

    Subject analysis set title
    week 36 - B cell rich Tocilizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell rich by histology classification and analysed as PP at week 36

    Subject analysis set title
    week 48 - B cell poor Rituximab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell poor by histology classification and analysed as PP at week 48

    Subject analysis set title
    week 48 - B cell poor Tocilizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell poor by histology classification and analysed as PP at week 48

    Subject analysis set title
    week 48 - B cell rich Rituximab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell rich by histology classification and analysed as PP at week 48

    Subject analysis set title
    week 48 - B cell rich Tocilizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell rich by histology classification and analysed as PP at week 48

    Subject analysis set title
    RTX+TOC, B cell poor, 16 weeks after
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    B cell poor patients who were non responders at visit 7-8 were switched to the other IMP and response was evaluated 16 weeks after this switch

    Subject analysis set title
    RTX+TOC, B cell rich, 16 weeks after
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    B cell rich patients who were non responders at visit 7-8 were switched to the other IMP and response was evaluated 16 weeks after this switch

    Subject analysis set title
    TOC+RTX, B cell poor, 16 weeks after
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    B cell poor patients who were non responders at visit 7-8 were switched to the other IMP and response was evaluated 16 weeks after this switch

    Subject analysis set title
    TOC+RTX, B cell rich, 16 weeks after
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    B cell rich patients who were non responders at visit 7-8 were switched to the other IMP and response was evaluated 16 weeks after this switch

    Primary: CDAI 50% Improvement

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    End point title
    		 CDAI 50% Improvement
    End point description
    Patients are deemed as Responders if their CDAI decreased by 50% or more from baseline
    End point type
    Primary
    End point timeframe
    Period 2: Baseline to Week 16 Period 3: Week 16 to Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab RTX+TOC, B cell poor, 16 weeks after RTX+TOC, B cell rich, 16 weeks after TOC+RTX, B cell poor, 16 weeks after TOC+RTX, B cell rich, 16 weeks after
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    14
    13
    8
    7
    Units: Responders
        Responder
    37
    44
    30
    33
    17
    23
    13
    16
    12
    20
    15
    14
    16
    21
    12
    12
    11
    19
    14
    9
    11
    21
    10
    14
    14
    16
    10
    14
    15
    16
    9
    13
    4
    5
    2
    3
    Statistical analysis title
    		 Primary: TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.114
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.106
         upper limit
    		 0.333
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.122
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.365
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA-seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.035
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.261
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.027
         upper limit
    		 0.496
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA-seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.89
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.017
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.272
         upper limit
    		 0.238
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.268
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.039
         upper limit
    		 0.496
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.135
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.132
         upper limit
    		 0.401
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA-seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0018
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.416
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.181
         upper limit
    		 0.651
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA-seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.026
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.317
         upper limit
    		 0.265
    Statistical analysis title
    		 RTX+TOC vs. TOC+RTX, B cell poor, week 16/20 +16
    Statistical analysis description
    Comparison of response in oatients who switched treatment
    Comparison groups
    RTX+TOC, B cell poor, 16 weeks after v TOC+RTX, B cell poor, 16 weeks after
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 RTX+TOC vs. TOC+RTX, B cell rich, week 16/20 + 16
    Statistical analysis description
    Comparison of response in patients who switched treatment
    Comparison groups
    RTX+TOC, B cell rich, 16 weeks after v TOC+RTX, B cell rich, 16 weeks after
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 24
    Comparison groups
    week 24 - B cell poor Rituximab v week 24 - B cell poor Tocilizumab
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.284
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.022
         upper limit
    		 0.546
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 24
    Comparison groups
    week 24 - B cell rich Rituximab v week 24 - B cell rich Tocilizumab
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.181
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.122
         upper limit
    		 0.484
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 36
    Comparison groups
    week 36 - B cell poor Rituximab v week 36 - B cell poor Tocilizumab
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.247
         upper limit
    		 0.301
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 36
    Comparison groups
    week 36 - B cell rich Rituximab v week 36 - B cell rich Tocilizumab
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.267
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.003
         upper limit
    		 0.537
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 48
    Comparison groups
    week 48 - B cell poor Rituximab v week 48 - B cell poor Tocilizumab
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.315
         upper limit
    		 0.15
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 48
    Comparison groups
    week 48 - B cell rich Rituximab v week 48 - B cell rich Tocilizumab
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.283
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.022
         upper limit
    		 0.588
    Statistical analysis title
    		 TOC vs. RTX, week 16
    Statistical analysis description
    Any pathotype
    Comparison groups
    Rituximab v Tocilizumab
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.106
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.048
         upper limit
    		 0.259
    Statistical analysis title
    		 TOC vs. RTX, week 48
    Statistical analysis description
    Any pathotype
    Comparison groups
    Rituximab v Tocilizumab
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.091
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.092
         upper limit
    		 0.273

    Primary: Ultrasound Power Doppler 12-max score, change from baseline

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    End point title
    		 Ultrasound Power Doppler 12-max score, change from baseline
    End point description
    End point type
    Primary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    17
    21
    17
    16
    Units: values
        least squares mean (standard error)
    -0.5 ± 0.7
    -2.1 ± 0.8
    -4.99 ± 0.74
    -5.72 ± 0.74
    0.3 ± 1.1
    -1.1 ± 1.1
    -1.4 ± 1.0
    -2.8 ± 1.1
    0.1 ± 1.1
    -1.2 ± 1.1
    -0.6 ± 1.3
    -2.9 ± 1.4
    0.1 ± 1.1
    -2.4 ± 1.4
    -1.5 ± 1.1
    -2.9 ± 1.3
    -0.2 ± 1.2
    -1.9 ± 1.3
    -0.6 ± 1.4
    -3.0 ± 1.7
    -4.9 ± 1.54
    -6.46 ± 1.79
    -5.42 ± 098
    -5.8 ± 0.98
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 4.8
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 4.6
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 4.7
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 6.4
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 6.5
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 4.9
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 5.6
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.29
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 7.1

    Secondary: Target CDAI (<10.1)

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    End point title
    		 Target CDAI (<10.1)
    End point description
    End point type
    Secondary
    End point timeframe
    Period 2: Baseline to Week 16 Period 3: Week 16 to Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: Patients
        Responder
    21
    36
    21
    31
    11
    19
    7
    12
    5
    16
    10
    10
    11
    17
    7
    8
    5
    15
    10
    5
    6
    16
    5
    10
    9
    13
    8
    11
    11
    14
    7
    12
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.174
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.036
         upper limit
    		 0.384
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.175
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.046
         upper limit
    		 0.396
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0036
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.348
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.136
         upper limit
    		 0.561
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.93
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.011
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.253
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.269
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.039
         upper limit
    		 0.5
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.122
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.122
         upper limit
    		 0.366
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00073
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.444
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.214
         upper limit
    		 0.673
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.54
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.094
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 0.172

    Secondary: DAS28 (ESR) <= 3.2

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    End point title
    		 DAS28 (ESR) <= 3.2
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: Responders
        Responders
    21
    36
    20
    33
    10
    18
    8
    13
    6
    17
    9
    10
    10
    14
    8
    11
    6
    15
    9
    7
    7
    17
    6
    13
    8
    14
    9
    11
    8
    16
    9
    12
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.176
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.031
         upper limit
    		 0.382
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.177
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.404
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0032
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.349
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.132
         upper limit
    		 0.567
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Tocilizumab v ITT week 16 - B cell rich (RNA_seq) Rituximab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.71
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.045
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.194
         upper limit
    		 0.283
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.095
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.196
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.032
         upper limit
    		 0.425
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.094
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.036
         upper limit
    		 0.476
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.412
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.178
         upper limit
    		 0.647
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.74
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.047
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.324

    Secondary: DAS28 (CRP) <= 3.2

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    End point title
    		 DAS28 (CRP) <= 3.2
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: Responders
        Responders
    26
    37
    18
    30
    12
    19
    12
    13
    7
    16
    14
    11
    12
    16
    10
    10
    7
    15
    12
    7
    9
    17
    10
    13
    11
    14
    7
    12
    9
    13
    7
    12
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.148
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.065
         upper limit
    		 0.36
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.056
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.183
         upper limit
    		 0.295
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.288
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.065
         upper limit
    		 0.51
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.087
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.338
         upper limit
    		 0.164
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.085
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.209
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.025
         upper limit
    		 0.443
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.112
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.149
         upper limit
    		 0.373
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0033
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.381
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.142
         upper limit
    		 0.621
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.68
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.344
         upper limit
    		 0.224

    Secondary: DAS28 (ESR) <= 2.6

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    End point title
    		 DAS28 (ESR) <= 2.6
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: Responders
        Responders
    10
    31
    9
    30
    6
    15
    2
    11
    3
    13
    3
    10
    6
    13
    2
    9
    3
    12
    3
    7
    3
    14
    2
    9
    5
    10
    3
    10
    3
    13
    4
    12
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Tocilizumab v ITT week 16 - B cell poor Rituximab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.208
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.396
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0047
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.294
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.107
         upper limit
    		 0.481
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.315
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.119
         upper limit
    		 0.512
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.245
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.041
         upper limit
    		 0.448
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.271
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.058
         upper limit
    		 0.485
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0052
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.327
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.109
         upper limit
    		 0.544
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0019
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.386
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.166
         upper limit
    		 0.607
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.066
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.261
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.016
         upper limit
    		 0.507

    Secondary: DAS28 (CRP) <= 2.6

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    End point title
    		 DAS28 (CRP) <= 2.6
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: Responders
        Responders
    12
    27
    11
    24
    7
    13
    4
    9
    4
    10
    4
    8
    7
    11
    4
    7
    4
    9
    4
    5
    3
    9
    2
    9
    3
    9
    4
    11
    5
    11
    5
    9
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.133
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.055
         upper limit
    		 0.321
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.169
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.026
         upper limit
    		 0.364
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.076
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.191
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.387
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.143
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.061
         upper limit
    		 0.346
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.177
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.036
         upper limit
    		 0.391
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.175
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.047
         upper limit
    		 0.397
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.056
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.235
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.015
         upper limit
    		 0.455
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.116
         upper limit
    		 0.357
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.116
         upper limit
    		 0.357

    Secondary: Good/Moderate EULAR DAS28 (ESR) response

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    End point title
    		 Good/Moderate EULAR DAS28 (ESR) response
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: Responders
        Responders
    60
    69
    38
    39
    25
    36
    25
    27
    21
    30
    24
    24
    24
    29
    23
    21
    20
    25
    22
    17
    17
    23
    14
    18
    17
    22
    15
    16
    16
    21
    15
    14
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.039
         upper limit
    		 0.401
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.113
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.075
         upper limit
    		 0.301
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0053
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.301
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.117
         upper limit
    		 0.485
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.028
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.171
         upper limit
    		 0.226
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0018
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.318
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.151
         upper limit
    		 0.485
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.171
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.021
         upper limit
    		 0.363
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00053
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.375
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.207
         upper limit
    		 0.543
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.109
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.096
         upper limit
    		 0.314

    Secondary: Good/Moderate EULAR DAS28 (CRP) response

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    End point title
    		 Good/Moderate EULAR DAS28 (CRP) response
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: Responders
        Responders
    54
    62
    34
    38
    22
    32
    23
    25
    18
    27
    23
    23
    21
    27
    21
    18
    17
    23
    21
    15
    16
    22
    14
    16
    18
    22
    13
    15
    15
    20
    12
    14
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Tocilizumab v ITT week 16 - B cell poor Rituximab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.054
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.202
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.403
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.109
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.319
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.298
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.087
         upper limit
    		 0.51
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.81
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.026
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.185
         upper limit
    		 0.238
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0029
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.332
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.525
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.54
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.105
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.341
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0015
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.389
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.186
         upper limit
    		 0.592
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.039
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.204
         upper limit
    		 0.283

    Secondary: CDAI, change from baseline

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    End point title
    		 CDAI, change from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: value
        least squares mean (standard deviation)
    -13.2 ± 1.3
    -14.8 ± 1.3
    -17.94 ± 1.13
    -22.82 ± 1.13
    -12.1 ± 1.9
    -15.7 ± 1.9
    -13.2 ± 2
    -14.2 ± 2.1
    -10.9 ± 2
    -17.2 ± 2
    -14.5 ± 2.1
    -14 ± 2.1
    -11.9 ± 1.9
    -17.9 ± 2.1
    -12.8 ± 2.1
    -12.6 ± 2.4
    -10.7 ± 2
    -18.6 ± 2.2
    -14 ± 2.2
    -12.1 ± 2.6
    -16.4 ± 1.9
    -21.0 ± 1.7
    -13.65 ± 2.27
    -17.2 ± 2.15
    -17.9 ± 1.6
    -22 ± 1.5
    -16.8 ± 1.78
    -21.8 ± 1.83
    -20 ± 1.55
    -22.8 ± 1.4
    -15.61 ± 2.06
    -22.51 ± 2.12
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 8.9
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.73
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.9
         upper limit
    		 6.9
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA-seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 12
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA-seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.88
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 5.6
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 11.7
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.93
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.7
         upper limit
    		 6.2
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA-seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0097
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 13.8
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA-seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.8
         upper limit
    		 5

    Secondary: DAS28 (ESR), change from baseline

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    End point title
    		 DAS28 (ESR), change from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: value
        least squares mean (standard deviation)
    -1.5 ± 0.1
    -2.5 ± 0.1
    -2.14 ± 0.18
    -3.29 ± 0.18
    -1.5 ± 0.2
    -2.6 ± 0.2
    -1.5 ± 0.2
    -2.6 ± 0.2
    -1.3 ± 0.2
    -2.8 ± 0.2
    -1.7 ± 0.2
    -2.4 ± 0.2
    -1.5 ± 0.2
    -2.8 ± 0.2
    -1.4 ± 0.2
    -2.6 ± 0.3
    -1.3 ± 0.2
    -3.0 ± 0.3
    -1.7 ± 0.2
    -2.4 ± 0.3
    -16.4 ± 1.9
    -21 ± 1.7
    -1.87 ± 0.29
    -2.82 ± 0.28
    -17.9 ± 1.6
    -22 ± 1.5
    -2.26 ± 0.25
    -3.39 ± 0.26
    -20 ± 1.55
    -22.8 ± 1.4
    -1.98 ± 0.34
    -3.39 ± 0.35
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Tocilizumab v ITT week 16 - B cell poor Rituximab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00063
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.7
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00088
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.7
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.000012
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 2.2
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 1.4
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.000053
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 2
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00095
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.9
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.000004
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.4
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 1.5

    Secondary: DAS28 (CRP), change from baseline

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    End point title
    		 DAS28 (CRP), change from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: value
        least squares mean (standard deviation)
    -1.4 ± 0.1
    -2 ± 0.1
    -1.82 ± 0.15
    -2.7 ± 0.15
    -1.3 ± 0.2
    -2.0 ± 0.2
    -1.5 ± 0.2
    -2.0 ± 0.2
    -1.1 ± 0.2
    -2.1 ± 0.2
    -1.6 ± 0.2
    -1.9 ± 0.2
    -1.3 ± 0.2
    -2.2 ± 0.2
    -1.4 ± 0.2
    -2.0 ± 0.2
    -1.1 ± 0.2
    -2.3 ± 0.2
    -1.6 ± 0.2
    -1.8 ± 0.3
    -1.6 ± 0.26
    -2.33 ± 0.23
    -1.64 ± 0.29
    -2.15 ± 0.27
    -1.98 ± 0.19
    -2.6 ± 0.19
    -1.88 ± 0.22
    -2.72 ± 0.22
    -2.03 ± 0.23
    -2.64 ± 0.21
    -1.76 ± 0.26
    -2.73 ± 0.27
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.032
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 1.3
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.059
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 1.1
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0021
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.6
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.9
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0054
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 1.5
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.076
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 1.2
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00033
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.9
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.9

    Secondary: HAQ score, change from baseline

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    End point title
    		 HAQ score, change from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: value
        least squares mean (standard deviation)
    -0.3 ± 0.1
    -0.4 ± 0.1
    -0.44 ± 0.1
    -0.66 ± 0.09
    -0.3 ± 0.1
    -0.4 ± 0.1
    -0.3 ± 0.1
    -0.4 ± 0.1
    -0.2 ± 0.1
    -0.2 ± 0.1
    -0.3 ± 0.1
    -0.5 ± 0.1
    -0.3 ± 0.1
    -0.4 ± 0.1
    -0.3 ± 0.1
    -0.3 ± 0.1
    -0.2 ± 0.1
    -0.2 ± 0.1
    -0.3 ± 0.1
    -0.4 ± 0.1
    -0.25 ± 0.14
    -0.45 ± 0.12
    -0.47 ± 0.11
    -0.38 ± 0.11
    -0.35 ± 0.13
    -0.65 ± 0.12
    -0.59 ± 0.14
    -0.55 ± 0.14
    -0.41 ± 0.14
    0.65 ± 0.13
    -0.58 ± 0.16
    -0.64 ± 0.16
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.3
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.4
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.91
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.2
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.085
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.5
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.4
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.88
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.3
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.3
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.24
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.4

    Secondary: FACIT score, change from baseline

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    End point title
    		 FACIT score, change from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: values
        least squares mean (standard deviation)
    4.6 ± 1
    6.7 ± 1
    7.5 ± 1.5
    8.3 ± 1.5
    1.6 ± 1.1
    5.6 ± 1.1
    8.5 ± 1.9
    7.8 ± 2.0
    2.1 ± 1.4
    4.9 ± 1.4
    6.9 ± 1.8
    8.3 ± 1.9
    1.7 ± 1.1
    5.6 ± 1.2
    7.8 ± 1.9
    7.4 ± 2.2
    2.3 ± 1.4
    4.2 ± 1.6
    6.0 ± 1.7
    8.1 ± 2.0
    1.95 ± 1.8
    6.6 ± 1.65
    10.3 ± 2.1
    6.2 ± 2
    5.08 ± 1.85
    7.84 ± 1.76
    14.0 ± 2.1
    8.1 ± 2.1
    5.58 ± 2.2
    7.11 ± 2
    11.4 ± 2.8
    8.4 ± 2.86
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Tocilizumab v ITT week 16 - B cell poor Rituximab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.2
         upper limit
    		 -0.8
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 6.3
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 1.2
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 3.8
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.021
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7
         upper limit
    		 -0.6
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.92
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.6
         upper limit
    		 6.2
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 2.4
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.5
         upper limit
    		 3.3

    Secondary: Ultrasound synovial Thickness 12-max score, change from baseline

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    End point title
    		 Ultrasound synovial Thickness 12-max score, change from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    17
    21
    17
    16
    Units: values
        least squares mean (standard deviation)
    -0.5 ± 0.9
    -1 ± 1
    -2.16 ± 1.25
    -1.37 ± 1.25
    -0.2 ± 1.5
    0.4 ± 1.6
    -0.8 ± 1.1
    -2.5 ± 1.2
    -1.4 ± 1.7
    2.2 ± 1.7
    -0.5 ± 1.0
    -4.1 ± 1.2
    -0.4 ± 1.5
    -1.3 ± 1.8
    -0.9 ± 1.2
    -2.6 ± 1.3
    -1.6 ± 1.8
    1.0 ± 2.0
    -0.5 ± 1.0
    -4.8 ± 1.4
    -2.16 ± 2.43
    2.62 ± 2.88
    2.32 ± 1.63
    3.35 ± 1.63
    Statistical analysis title
    		 TOC vs RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.82
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 4.1
    Statistical analysis title
    		 TOC vs RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 5
    Statistical analysis title
    		 TOC vs RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 1.6
    Statistical analysis title
    		 TOC vs RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 6.9
    Statistical analysis title
    		 TOC vs RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.72
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 5.9
    Statistical analysis title
    		 TOC vs RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 5.4
    Statistical analysis title
    		 TOC vs RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.3
         upper limit
    		 2.9
    Statistical analysis title
    		 TOC vs RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 8.1

    Secondary: SF36 - Physical Component Summary

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    End point title
    		 SF36 - Physical Component Summary
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: values
        least squares mean (standard deviation)
    4.9 ± 1.1
    8.3 ± 1.2
    9.4 ± 1.6
    15.3 ± 1.7
    4.0 ± 1.5
    7.3 ± 1.5
    7.0 ± 1.9
    8.5 ± 2.1
    3.5 ± 1.5
    4.3 ± 1.5
    6.9 ± 1.9
    10.9 ± 2.1
    4.3 ± 1.5
    8.3 ± 1.7
    6.3 ± 1.8
    6.4 ± 2.1
    3.7 ± 1.5
    4.2 ± 1.7
    6.2 ± 1.8
    8.9 ± 2.1
    7.7 ± 2
    8.73 ± 1.94
    11.7 ± 2.4
    10 ± 2.34
    7.96 ± 2.36
    13.3 ± 2.3
    11.2 ± 2.95
    10.16 ± 2.95
    8.6 ± 2.5
    16.2 ± 2.4
    10.22 ± 2.98
    13.27 ± 2.07
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Tocilizumab v ITT week 16 - B cell poor Rituximab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.4
         upper limit
    		 0.9
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.2
         upper limit
    		 4.1
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.72
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 3.4
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.6
         upper limit
    		 1.6
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.5
         upper limit
    		 0.5
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.98
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 5.5
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 4.1
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 2.8

    Secondary: SF36 - Mental Component Summary

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    End point title
    		 SF36 - Mental Component Summary
    End point description
    End point type
    Secondary
    End point timeframe
    Timeframe 2: Week 16 Timeframe 3: Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: values
        least squares mean (standard deviation)
    1.7 ± 1.2
    3.2 ± 1.3
    4.54 ± 1.66
    4.78 ± 1.7
    -0.7 ± 1.6
    2.1 ± 1.6
    5.4 ± 2.2
    3.3 ± 2.4
    0.9 ± 1.8
    4.5 ± 1.8
    4.4 ± 2.3
    3.0 ± 2.5
    -0.7 ± 1.6
    2.7 ± 1.8
    4.4 ± 2.3
    4.2 ± 2.6
    1.0 ± 1.8
    5.1 ± 2.1
    3.1 ± 2.3
    4.2 ± 2.8
    -2.66 ± 2.86
    3.91 ± 2.67
    2.53 ± 2.69
    5.7 ± 2.61
    -0.98 ± 2.2
    3.82 ± 2.15
    7.1 ± 2.36
    3.25 ± 2.36
    1.54 ± 2.7
    4.7 ± 2.54
    7.75 ± 2.68
    3.37 ± 2.77
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 1.7
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 8.5
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.8
         upper limit
    		 1.5
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.68
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.4
         upper limit
    		 8.2
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.1
         upper limit
    		 1.4
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.96
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.7
         upper limit
    		 7.1
    Statistical analysis title
    		 TOC vs. RTX, B cell poor (RNA seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.14
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.6
         upper limit
    		 1.4
    Statistical analysis title
    		 TOC vs. RTX, B cell rich (RNA seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 6.3

    Secondary: SHSS total score, change from baseline

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    End point title
    		 SHSS total score, change from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24 Week 48
    End point values
    		 week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    21
    27
    18
    20
    17
    21
    17
    16
    Units: score
        least squares mean (standard deviation)
    0.09 ± 0.58
    1.2 ± 0.43
    0.36 ± 0.21
    0.31 ± 0.19
    0.02 ± 0.69
    1.15 ± 0.56
    0.36 ± 0.2
    0.25 ± 0.21
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 24
    Comparison groups
    week 24 - B cell poor Rituximab v week 24 - B cell poor Tocilizumab
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.61
         upper limit
    		 0.38
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 24
    Comparison groups
    week 24 - B cell rich Rituximab v week 24 - B cell rich Tocilizumab
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 0.64
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 48
    Comparison groups
    week 48 - B cell rich Rituximab v week 48 - B cell rich Tocilizumab
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.73
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 48
    Comparison groups
    week 48 - B cell poor Tocilizumab v week 48 - B cell poor Rituximab
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.02
         upper limit
    		 0.75

    Secondary: SHSS Erosion score, change from baseline

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    End point title
    		 SHSS Erosion score, change from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24 Week 48
    End point values
    		 week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    21
    27
    18
    20
    17
    21
    17
    16
    Units: score
        arithmetic mean (standard deviation)
    0.13 ± 0.24
    0.39 ± 0.18
    0.36 ± 0.16
    0.04 ± 0.15
    0.08 ± 0.29
    0.32 ± 0.24
    0.36 ± 0.18
    0.05 ± 0.19
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 24
    Comparison groups
    week 24 - B cell poor Rituximab v week 24 - B cell poor Tocilizumab
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.89
         upper limit
    		 0.37
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 48
    Comparison groups
    week 48 - B cell poor Rituximab v week 48 - B cell poor Tocilizumab
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.04
         upper limit
    		 0.55
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 24
    Comparison groups
    week 24 - B cell rich Rituximab v week 24 - B cell rich Tocilizumab
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.79
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 48
    Comparison groups
    week 48 - B cell rich Rituximab v week 48 - B cell rich Tocilizumab
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.85

    Secondary: SHSS Joint Space Narrowing score

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    End point title
    		 SHSS Joint Space Narrowing score
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24 Week 48
    End point values
    		 week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    21
    27
    18
    20
    17
    21
    17
    16
    Units: score
        arithmetic mean (standard deviation)
    -0.08 ± 0.37
    0.61 ± 0.28
    0.23 ± 0.19
    0.23 ± 0.17
    -0.12 ± 0.44
    0.58 ± 0.35
    0.22 ± 0.2
    0.2 ± 0.21
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 24
    Comparison groups
    week 24 - B cell poor Rituximab v week 24 - B cell poor Tocilizumab
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.65
         upper limit
    		 0.28
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 48
    Comparison groups
    week 48 - B cell poor Rituximab v week 48 - B cell poor Tocilizumab
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.89
         upper limit
    		 0.5
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 24
    Comparison groups
    week 24 - B cell rich Rituximab v week 24 - B cell rich Tocilizumab
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 0.54
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 48
    Comparison groups
    week 48 - B cell rich Rituximab v week 48 - B cell rich Tocilizumab
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 0.62

    Other pre-specified: CDAI 50% improvement and CDAI<10.1

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    End point title
    		 CDAI 50% improvement and CDAI<10.1
    End point description
    A patient must have improved by 50% from baseline AND have a low disease activty (CDAI<10.1) to be deemed as a responder
    End point type
    Other pre-specified
    End point timeframe
    Period 2: Baseline to Week 16 Period 3: Week 16 to Week 48
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab ITT week 16 - B cell poor (RNA_seq) Rituximab ITT week 16 - B cell poor (RNA_seq) Tocilizumab ITT week 16 - B cell rich (RNA_seq) Rituximab ITT week 16 - B cell rich (RNA_seq) Tocilizumab PP week 16 - B cell poor Rituximab PP week 16 - B cell poor Tocilizumab PP week 16 - B cell rich Rituximab PP week 16 - B cell rich Tocilizumab PP week 16 - B cell poor (RNA_seq) Rituximab PP week 16 - B cell poor (RNA_seq) Tocilizumab PP week 16 - B cell rich (RNA_seq) RItuximab PP week 16 - B cell rich (RNA_seq) Tocilizumab week 24 - B cell poor Rituximab week 24 - B cell poor Tocilizumab week 24 - B cell rich Rituximab week 24 - B cell rich Tocilizumab week 36 - B cell poor Rituximab week 36 - B cell poor Tocilizumab week 36 - B cell rich Rituximab week 36 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    82
    79
    42
    42
    38
    41
    33
    31
    33
    32
    30
    29
    37
    30
    31
    23
    32
    25
    28
    19
    21
    27
    18
    20
    20
    22
    17
    16
    17
    21
    17
    16
    Units: Patients
        Responder
    17
    35
    20
    30
    9
    19
    5
    11
    4
    16
    7
    9
    9
    17
    5
    7
    4
    15
    7
    4
    5
    15
    5
    10
    9
    12
    7
    11
    11
    14
    6
    12
    Statistical analysis title
    		 TOC vs RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.035
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.227
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.023
         upper limit
    		 0.43
    Statistical analysis title
    		 TOC vs RTX, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.085
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.203
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.005
         upper limit
    		 0.411
    Statistical analysis title
    		 TOC vs RTX, B cell poor (RNA-seq), ITT
    Comparison groups
    ITT week 16 - B cell poor (RNA_seq) Rituximab v ITT week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0012
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.379
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.173
         upper limit
    		 0.585
    Statistical analysis title
    		 TOC vs RTX, B cell rich (RNA-seq), ITT
    Comparison groups
    ITT week 16 - B cell rich (RNA_seq) Rituximab v ITT week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.077
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.149
         upper limit
    		 0.303
    Statistical analysis title
    		 TOC vs RTX, B cell poor, PP
    Comparison groups
    PP week 16 - B cell poor Rituximab v PP week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0069
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.323
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.099
         upper limit
    		 0.548
    Statistical analysis title
    		 TOC vs RTX, B cell rich, PP
    Comparison groups
    PP week 16 - B cell rich Rituximab v PP week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.143
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.085
         upper limit
    		 0.371
    Statistical analysis title
    		 TOC vs RTX, B cell poor (RNA-seq), PP
    Comparison groups
    PP week 16 - B cell poor (RNA_seq) Rituximab v PP week 16 - B cell poor (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00022
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.475
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.251
         upper limit
    		 0.699
    Statistical analysis title
    		 TOC vs RTX, B cell rich (RNA-seq), PP
    Comparison groups
    PP week 16 - B cell rich (RNA_seq) RItuximab v PP week 16 - B cell rich (RNA_seq) Tocilizumab
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.039
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.283
         upper limit
    		 0.204

    Other pre-specified: AUC of mean improvement in DAS28 (ESR)

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    End point title
    		 AUC of mean improvement in DAS28 (ESR)
    End point description
    Area under the curve (AUC) of mean improvement in DAS28 over time between 0 and 16 weeks and between 0 and 48 weeks
    End point type
    Other pre-specified
    End point timeframe
    Timeframe 2: week 16 Timeframe 3: week 48
    End point values
    		 ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    38
    41
    33
    31
    17
    21
    17
    16
    Units: area
        number (not applicable)
    17.1
    31.9
    13.9
    34.0
    83.3
    134.0
    75.5
    132.4
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 16
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.01
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 16
    Comparison groups
    ITT week 16 - B cell rich Rituximab v ITT week 16 - B cell rich Tocilizumab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.01
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 48
    Comparison groups
    week 48 - B cell poor Rituximab v week 48 - B cell poor Tocilizumab
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 48
    Comparison groups
    week 48 - B cell rich Rituximab v week 48 - B cell rich Tocilizumab
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Other pre-specified: AUC of mean improvement in DAS28 (CRP)

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    End point title
    		 AUC of mean improvement in DAS28 (CRP)
    End point description
    Area under the curve (AUC) of mean improvement in DAS28 over time between 0 and16 weeks and between 0 and 48 weeks
    End point type
    Other pre-specified
    End point timeframe
    Timeframe 2: week 16 Timeframe 3: week 48
    End point values
    		 ITT week 16 - B cell poor Rituximab ITT week 16 - B cell poor Tocilizumab ITT week 16 - B cell rich Rituximab ITT week 16 - B cell rich Tocilizumab week 48 - B cell poor Rituximab week 48 - B cell poor Tocilizumab week 48 - B cell rich Rituximab week 48 - B cell rich Tocilizumab
    Number of subjects analysed
    38
    41
    33
    31
    17
    21
    17
    16
    Units: area
        number (not applicable)
    15.6
    23.5
    13.1
    26.8
    73.6
    107.2
    69.0
    103.6
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 16
    Comparison groups
    ITT week 16 - B cell poor Rituximab v ITT week 16 - B cell poor Tocilizumab
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.01
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 16
    Comparison groups
    ITT week 16 - B cell rich Tocilizumab v ITT week 16 - B cell rich Rituximab
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.01
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, B cell poor, week 48
    Comparison groups
    week 48 - B cell poor Rituximab v week 48 - B cell poor Tocilizumab
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, B cell rich, week 48
    Comparison groups
    week 48 - B cell rich Rituximab v week 48 - B cell rich Tocilizumab
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Other pre-specified: CD20 score

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    End point title
    		 CD20 score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Timeframe 1: Baseline Timeframe 2: week 16
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab
    Number of subjects analysed
    41
    24
    41
    24
    Units: score
        arithmetic mean (standard deviation)
    1.88 ± 1.4
    1.67 ± 1.3
    0.35 ± 0.8
    1.33 ± 1.3
    Statistical analysis title
    		 Week 16 vs. Baseline, Rituximab
    Comparison groups
    Rituximab v Rituximab
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Week 16 vs. Baseline, Tocilizumab
    Comparison groups
    Tocilizumab v Tocilizumab
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, change from baseline
    Comparison groups
    Tocilizumab v Tocilizumab v Rituximab v Rituximab
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Other pre-specified: CD138 score

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    End point title
    		 CD138 score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Timeframe 1: Baseline Timeframe 2: week 16
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab
    Number of subjects analysed
    41
    24
    41
    24
    Units: score
        arithmetic mean (standard deviation)
    1.68 ± 1.3
    1.58 ± 1.4
    0.35 ± 0.8
    1.33 ± 1.3
    Statistical analysis title
    		 Week 16 vs. Baseline, Rituximab
    Comparison groups
    Rituximab v Rituximab
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Week 16 vs. Baseline, Tocilizumab
    Comparison groups
    Tocilizumab v Tocilizumab
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, change from baseline
    Comparison groups
    Tocilizumab v Tocilizumab v Rituximab v Rituximab
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: CD68L score

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    End point title
    		 CD68L score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Timeframe 1: Baseline Timeframe 2: week 16
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab
    Number of subjects analysed
    41
    24
    41
    24
    Units: score
        arithmetic mean (standard deviation)
    1.2 ± 1
    1.46 ± 1.1
    1.07 ± 0.9
    1.38 ± 1.1
    Statistical analysis title
    		 Week 16 vs. Baseline, Rituximab
    Comparison groups
    Rituximab v Rituximab
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Week 16 vs. Baseline, Tocilizumab
    Comparison groups
    Tocilizumab v Tocilizumab
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, change vs. baseline
    Comparison groups
    Tocilizumab v Tocilizumab v Rituximab v Rituximab
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Confidence interval

    Other pre-specified: CD68SL score

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    End point title
    		 CD68SL score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Timeframe 1: Baseline Timeframe 2: week 16
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab
    Number of subjects analysed
    41
    24
    41
    24
    Units: score
        arithmetic mean (standard deviation)
    1.88 ± 0.8
    1.92 ± 1
    1.3 ± 0.6
    0.88 ± 0.7
    Statistical analysis title
    		 Week 16 vs. Baseline, Rituximab
    Comparison groups
    Rituximab v Rituximab
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Week 16 vs. Baseline, Tocilizumab
    Comparison groups
    Tocilizumab v Tocilizumab
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, change from baseline
    Comparison groups
    Tocilizumab v Tocilizumab v Rituximab v Rituximab
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Other pre-specified: CD3 score

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    End point title
    		 CD3 score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Timeframe 1: Baseline Timeframe 2: week 16
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab
    Number of subjects analysed
    41
    24
    41
    24
    Units: score
        arithmetic mean (standard deviation)
    1.63 ± 1.1
    1.58 ± 1.1
    1.52 ± 1.2
    1.42 ± 1.2
    Statistical analysis title
    		 Week 16 vs. baseline, Rituximab
    Comparison groups
    Rituximab v Rituximab
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Week 16 vs. baseline, Tocilizumab
    Comparison groups
    Tocilizumab v Tocilizumab
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, change from baseline
    Comparison groups
    Tocilizumab v Tocilizumab v Rituximab v Rituximab
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Confidence interval

    Other pre-specified: CD79a score

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    End point title
    		 CD79a score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Timeframe 1: Baseline Timeframe 2: week 16
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab
    Number of subjects analysed
    41
    24
    41
    24
    Units: score
        arithmetic mean (standard deviation)
    1.77 ± 1.4
    1.54 ± 1.3
    0.9 ± 1.1
    1.47 ± 1.2
    Statistical analysis title
    		 Week 16 vs. baseline, Rituximab
    Comparison groups
    Rituximab v Rituximab
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Week 16 vs. baseline, Tocilizumab
    Comparison groups
    Tocilizumab v Tocilizumab
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, change from baseline
    Comparison groups
    Tocilizumab v Tocilizumab v Rituximab v Rituximab
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Other pre-specified: Synovial score

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    End point title
    		 Synovial score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Timeframe 1: Baseline Timeframe 2: week 16
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab
    Number of subjects analysed
    41
    24
    41
    24
    Units: score
        arithmetic mean (standard deviation)
    4.63 ± 2.5
    4.38 ± 2.8
    3.23 ± 2
    3.46 ± 2.4
    Statistical analysis title
    		 Week 16 vs. baseline, Rituximab
    Comparison groups
    Rituximab v Rituximab
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Week 16 vs. baseline, Tocilizumab
    Comparison groups
    Tocilizumab v Tocilizumab
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 TOC vs. RTX, change from baseline
    Comparison groups
    Tocilizumab v Tocilizumab v Rituximab v Rituximab
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Confidence interval

    Other pre-specified: CD21 status

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    End point title
    		 CD21 status
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Timeframe 1: Baseline Timeframe 2: week 16
    End point values
    		 Rituximab Tocilizumab Rituximab Tocilizumab
    Number of subjects analysed
    41
    24
    41
    24
    Units: Patients
    35
    21
    39
    20
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were recorded from the time of the first trial specific assessment/procedure was undertaken (at the screening visit) until LPLV (+30 days where patients only participated up until week 48 (i.e. the end of the trial treatment period)).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Patients on rituximab at the time of the event

    Reporting group title
    Tocilizumab
    Reporting group description
    		 Patients on tocilizumab at the time of the event

    Serious adverse events
    		 Rituximab Tocilizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 108 (7.41%)
    18 / 117 (15.38%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Drainage of cyst around dental implant, removal implant
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Drainage of Pilonidal Abscess
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospitalisation following (L) 4th toe amputation and (R) 3rd toe PIP fusion
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Total Knee Replacement
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain requiring hospital admission
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine Release Syndrome
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Rt side Pleural effusion
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of COPD
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    RE-admission to hospital, post MI. Repeat coronary angiogram
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Persistent Chest Pain, Mild Left Ventricular impairment
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain during cardiac rehabilitation
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden onset chest pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure, Fracture of the Humerous/Femur
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Corneal melt
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea - salmonella
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Abdominal pain (urinoma)
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract infection
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Parathyroid adenoma requiring intervention
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in left leg (scan showed no blood clot)
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospitalisation for elective surgery to left Hallux vagus (osteotomy)
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pilonidal sinus caused by an infectious agent
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Rituximab Tocilizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 108 (52.78%)
    72 / 117 (61.54%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Synovial cyst
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Vascular disorders
    Angina
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Bleeding
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Blood pressure high
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 117 (1.71%)
         occurrences all number
    0
    2
    Bruising of foot
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Capillary disorder
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 117 (1.71%)
         occurrences all number
    0
    2
    Dizziness postural
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Dot hemorrhages
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Felt faint
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Foot ulcer
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    2
    Hematoma infection
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 117 (0.85%)
         occurrences all number
    4
    1
    Light headedness
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 117 (0.85%)
         occurrences all number
    2
    1
    Nose bleed
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Purpura
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    PV bleeding
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 117 (0.85%)
         occurrences all number
    2
    1
    Rectal bleeding
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Skin sores
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Spotting vaginal
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Vasculitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Artificial crown procedure
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Cataract operation
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Coronary arterial stent insertion
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Cyst removal
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Drainage of abscess
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Foot surgery
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Hernia repair
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Knee total replacement
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 117 (0.00%)
         occurrences all number
    2
    0
    Osteotomy
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Removal of foreign body
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    2
    Tooth repair
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    3 / 108 (2.78%)
    0 / 117 (0.00%)
         occurrences all number
    4
    0
    Ankle oedema
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Asthenia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Axillary pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 117 (1.71%)
         occurrences all number
    0
    2
    Edema of lower extremities
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Extravasation of drug
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 108 (1.85%)
    3 / 117 (2.56%)
         occurrences all number
    2
    5
    Fever
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Flank pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Flu like symptoms
         subjects affected / exposed
    5 / 108 (4.63%)
    2 / 117 (1.71%)
         occurrences all number
    5
    2
    General symptoms
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Generalised aching
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 117 (1.71%)
         occurrences all number
    0
    2
    Localised superficial swelling, mass or lump
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Oedema of lower extremities
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    3 / 108 (2.78%)
    0 / 117 (0.00%)
         occurrences all number
    3
    0
    Peripheral edema
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pitting oedema
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Suprapubic pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Swelling of feet
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Swelling of fingers
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Swelling of legs
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Thoracalgia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Allergic skin reaction
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Angioedema
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Asthmatic attack
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Exacerbation of asthma
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Hay fever
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Infusion related reaction
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Rheumatoid arthritis flare up
         subjects affected / exposed
    1 / 108 (0.93%)
    2 / 117 (1.71%)
         occurrences all number
    1
    2
    Seasonal allergy
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Genital ulceration
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Metorrhagia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Vaginal discharge
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    2
    Vaginal prolapse
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Acute nasal congestion
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Breathlessness
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 117 (1.71%)
         occurrences all number
    0
    2
    Chest infection
         subjects affected / exposed
    8 / 108 (7.41%)
    12 / 117 (10.26%)
         occurrences all number
    11
    14
    Cold
         subjects affected / exposed
    5 / 108 (4.63%)
    6 / 117 (5.13%)
         occurrences all number
    5
    6
    Common cold
         subjects affected / exposed
    7 / 108 (6.48%)
    4 / 117 (3.42%)
         occurrences all number
    7
    5
    COPD exacerbation
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 117 (1.71%)
         occurrences all number
    0
    2
    Cough
         subjects affected / exposed
    6 / 108 (5.56%)
    2 / 117 (1.71%)
         occurrences all number
    6
    2
    Dry cough
         subjects affected / exposed
    3 / 108 (2.78%)
    2 / 117 (1.71%)
         occurrences all number
    3
    2
    Dyspnoea
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 108 (2.78%)
    2 / 117 (1.71%)
         occurrences all number
    3
    2
    Nasal mucosal blistering
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Nasal ulcer
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pleurisy
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Runny nose
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Shortness of breath
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 108 (4.63%)
    5 / 117 (4.27%)
         occurrences all number
    5
    5
    Psychiatric disorders
    Alzheimer's disease
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Depressed state
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Sleeplessness
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Stress
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Investigations
    Abnormal LFTs
         subjects affected / exposed
    0 / 108 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    0
    4
    ALT increased
         subjects affected / exposed
    1 / 108 (0.93%)
    8 / 117 (6.84%)
         occurrences all number
    1
    11
    Anti-transglutaminase antibody increased
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    AST increased
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 117 (1.71%)
         occurrences all number
    0
    3
    Bilirubin increased
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Biopsy of lymph node
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Cerebellum MRI signal changes
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Cervical smear test abnormal
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Colonoscopy
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Creatinine abnormal NOS
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Creatinine high
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Cyst aspiration
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    ECG normal
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin low
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 117 (0.00%)
         occurrences all number
    2
    0
    Heart rate increased
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Hemoglobin low
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Knee arthroscopy
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Low density lipoprotein cholesterol high
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Low platelets
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    2
    Mean corpuscular volume increased
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Potassium low
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Thyroid stimulating hormone
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Transaminases increased
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Vitamin D low
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Weight loss
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Accidental overdose (therapeutic agent)
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Bee sting
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Biceps tendon rupture
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Bite
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 117 (0.85%)
         occurrences all number
    2
    1
    Bruising
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Cut wound
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    2 / 108 (1.85%)
    5 / 117 (4.27%)
         occurrences all number
    3
    5
    Infusion related reaction
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Open wound of tooth (broken), uncomplicated
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pain post biopsy
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Scratch eye
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Tronchanteric bursitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Wasp sting
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Wound
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Demyelination
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Facial neuralgia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    9 / 108 (8.33%)
    4 / 117 (3.42%)
         occurrences all number
    11
    5
    Headache recurrent
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Migraine with aura
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Neurological impairment
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Pain head
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Sensory loss
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Trembling
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Leucopenia
         subjects affected / exposed
    1 / 108 (0.93%)
    2 / 117 (1.71%)
         occurrences all number
    1
    2
    Lymphangitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 108 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    0
    4
    Normocytic anaemia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Swollen glands
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Ear disorder NOS
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Otalgia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Eye disorders
    Bilateral cataracts
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Blepharitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Blurred vision
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 117 (1.71%)
         occurrences all number
    0
    3
    Dry eyes
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 117 (0.00%)
         occurrences all number
    3
    0
    Lesion corneal
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Ocular pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Subconjunctival hemorrhage
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Xerophthalmia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal bloating
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Abdominal pain
         subjects affected / exposed
    1 / 108 (0.93%)
    2 / 117 (1.71%)
         occurrences all number
    1
    2
    Abdominal pain lower
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Abdominal tenderness
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Acid reflux (esophageal)
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Alternation between constipation and diarrhoea
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Bloody diarrhoea
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Colonic tubular adenoma
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 117 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    4 / 108 (3.70%)
    2 / 117 (1.71%)
         occurrences all number
    4
    2
    Dyspepsia
         subjects affected / exposed
    1 / 108 (0.93%)
    3 / 117 (2.56%)
         occurrences all number
    1
    3
    Dysphagia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Emesis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Epigastralgia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Epigastric discomfort
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Food poisoning
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Indigestion
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Itchy throat
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Lip ulcer
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Loose stools
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 117 (0.00%)
         occurrences all number
    2
    0
    Mouth ulcer
         subjects affected / exposed
    2 / 108 (1.85%)
    7 / 117 (5.98%)
         occurrences all number
    2
    8
    Nausea
         subjects affected / exposed
    3 / 108 (2.78%)
    2 / 117 (1.71%)
         occurrences all number
    3
    2
    Nausea vomiting and diarrhoea
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    2
    1
    Oral mucosa bleeding
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Sensitive mouth
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Sickness/nausea
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Sore mouth
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Sore throat
         subjects affected / exposed
    2 / 108 (1.85%)
    3 / 117 (2.56%)
         occurrences all number
    2
    3
    Stomatitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Throat pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Tongue ulceration
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Ulcer aphthous oral
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Upset stomach
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    4 / 108 (3.70%)
    1 / 117 (0.85%)
         occurrences all number
    7
    1
    Watery Diarrhoea
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Biliary microlithiasis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Dilatation biliary tract
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Hypertransaminasemia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Butterfly rash
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Cutaneous vasculitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Dry scalp
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Dysaesthesia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    2
    Erythema
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 117 (0.00%)
         occurrences all number
    2
    0
    Erythema facial
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Extensive rash of forearm
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Folliculitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Generalised itching
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Hair loss
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Hidradenitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Infected skin ulcer
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Irritation skin
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Itching
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 117 (0.00%)
         occurrences all number
    2
    0
    Itchy rash
         subjects affected / exposed
    4 / 108 (3.70%)
    0 / 117 (0.00%)
         occurrences all number
    4
    0
    Itchy scalp
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Macular rash
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 117 (0.00%)
         occurrences all number
    2
    0
    Nail discomfort
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Nail infection
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Papular rash
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Pins and needles
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Prickly heat
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Pruritic rash
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    1 / 108 (0.93%)
    6 / 117 (5.13%)
         occurrences all number
    1
    6
    Rash on face
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Redness of face
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Scalp rash
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Skin infection
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Skin lesion
         subjects affected / exposed
    1 / 108 (0.93%)
    2 / 117 (1.71%)
         occurrences all number
    1
    2
    Skin rash
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Tingling sensation
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    2
    2
    Urticarial
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Urticarial rash
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Vasculitic rash
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Skin lesion NOS
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Cystitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pelvic pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Urinary frequency
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 117 (0.00%)
         occurrences all number
    2
    0
    Urinary infection
         subjects affected / exposed
    2 / 108 (1.85%)
    5 / 117 (4.27%)
         occurrences all number
    3
    5
    Urinary retention
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 108 (2.78%)
    9 / 117 (7.69%)
         occurrences all number
    4
    11
    UTI
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Achilles tendon pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Arthralgia aggravated
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Avascular necrosis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    3 / 108 (2.78%)
    3 / 117 (2.56%)
         occurrences all number
    3
    3
    Calf pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Fascitis plantar
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Finger cramps
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Frozen shoulder
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Joint clicking
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Joint infection
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Knee effusion
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Knee ligament injury
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Knee pain
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 117 (0.85%)
         occurrences all number
    2
    1
    Leg pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Low back pain
         subjects affected / exposed
    4 / 108 (3.70%)
    1 / 117 (0.85%)
         occurrences all number
    4
    1
    Muscle twitch
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Neck pain (with radiation)
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Osteoarthritis of cervical spine
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Pain in (l) knee
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pain in (l) shoulder
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pain in (r) elbow
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Pain in arm
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    2
    0
    Pain in hip
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pain in lumbar spine
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pain in toe
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Shoulder pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Swollen wrists
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Wrist pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Infections and infestations
    Abscess on buttock
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Acute bronchitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Acute infective bronchitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Acute sinusitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Acute tracheobronchitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Asymptomatic bacteriuria
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Breast abscess
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    2 / 108 (1.85%)
    3 / 117 (2.56%)
         occurrences all number
    2
    4
    Cellulitis
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 117 (1.71%)
         occurrences all number
    0
    2
    Cellulitis of legs
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Cold sores
         subjects affected / exposed
    1 / 108 (0.93%)
    4 / 117 (3.42%)
         occurrences all number
    1
    4
    Cold sores lip
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Cold sores mouth
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Coryza
         subjects affected / exposed
    4 / 108 (3.70%)
    0 / 117 (0.00%)
         occurrences all number
    4
    0
    Dental abscess
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 117 (0.00%)
         occurrences all number
    2
    0
    Ear infection
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Epididymitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Eye infection
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    2
    1
    Fever blister
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Flu
         subjects affected / exposed
    4 / 108 (3.70%)
    1 / 117 (0.85%)
         occurrences all number
    4
    1
    Foot infection
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Fungal skin infection
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 108 (0.93%)
    3 / 117 (2.56%)
         occurrences all number
    1
    3
    Gingivitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Haemophilus influenza infection
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Herpes simplex
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Infected corn
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Infected insect bite
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Infected toe
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Laryngitis
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 117 (1.71%)
         occurrences all number
    0
    3
    Mastitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Mycosis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Oral thrush
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Otitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Perineal abscess
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    2
    Periorbital cellulitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Respiratory infection
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Shingles
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Sinus infection
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Sinusitis
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 117 (1.71%)
         occurrences all number
    0
    2
    Streptococcal pharyngitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Thrush vaginal
         subjects affected / exposed
    1 / 108 (0.93%)
    2 / 117 (1.71%)
         occurrences all number
    1
    2
    Tooth abscess
         subjects affected / exposed
    0 / 108 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    0
    3
    Tooth infection
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 117 (0.85%)
         occurrences all number
    1
    1
    Vaginal candidiasis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Vaginal mycosis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Wound infection
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences all number
    1
    0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2013
    Update to Protocol: Change to biopsy schedule and primary end point (24 weeks to 16 weeks) Revision (reduction) of study blood assessments Addition of use of PICs Clarification of fourth unknown stratum for randomisation procedures Clarification of SAE reporting period Clarification of procedures for early withdrawal Clarification of events not to be reported as SAEs Clarification of treatment period and observation period Clarification of permitted steroid use Collection of new data fields; previous anti-TNF and total Chol, HDL, LDL, tryglycerides. Updates to PIS: Less prescriptive information on trial hypothesis to reduce patient bias Clarification of potential to switch medication from Weeks 16 to 48 Clarification of treatment period and observation period and visit schedules Clarification for treatment after trial has ended. Inclusion of emergency contact details. Other formatting changes, clarifications, corrections to the above documents.
    03 Sep 2013
    Addition of trial sites Change of PI (Barts Health)
    02 May 2014
    1. Expansion of synovial biopsy technique to allow use of arthroscopic biopsy as well as US guided needle synovial biopsy 2. Additional exclusion criteria (#4- Prior exposure to Rituximab or Tocilizumab for the treatment of RA) 3. Amendment to exclusion criteria already listed to include latex allergy or allergy to any excipients of Rituximab and Tocilizumab 4. Clarifications to procedures for administration of IMPs (specifically Rituximab) 5. Relaxation of requirements/restrictions for corticosteroid use during treatment 6. Amendment to requirements for routine bloods at screening and biopsy time points 7. Clarifications on treatment schedule for both IMPs 8. Amendment to requirement for x-ray of hands and feet at Baseline visit 9. Addition of instructions to conduct tender joint (TJC) and swollen joint count (SJC). 10. Extra study specific blood time point at week 28 and clarification of potential for change to study blood schedule (in line with any potential switch in trial treatment as per protocol). 11. Additional PAXgene RNA tube at Biopsy visit, Week 16, Week 48 and Week 96 time-points. 12. Amendment to criteria for Early Withdrawal and clarification that this refers specifically to treatment cessation 13. Clarification on procedures for data collection and follow up for Withdrawn Subjects 14. Clarification of procedures for SAE reporting post cessation of treatment 15. Additional secondary endpoints 16. Clarification of no safety endpoints 17. APPLICABLE only to lead site (Mile End Hospital, Barts Health): Revision of optional biopsy time point so that, for any patient, who chooses to have any subsequent biopsy [beyond week 16 visit], a biopsy may be taken at such time that a patient switches treatment (ie deemed a non-responder).
    21 Oct 2014
    Addition of trial sites (Southampton and Basildon)
    26 Nov 2014
    Addition of trial sites (Southend and Aintree/Liverpool)
    09 Jan 2015
    1. Addition of optional biopsy consent form 2. Protocol: Addition of faster infusion schedule for second and subsequent Rituximab infusion, as per Rituximab SmPC. 3. Protocol: Addition of a time point (within 4 weeks prior to Visit 3 Baseline) where restrictions apply for the use of corticosteroids. 4. Protocol: Hepatitis B screening has been made mandatory to be consistent with SmPC for Rituximab (updated on 23/05/2014). Exclusion criteria #11 amended to "Known HIV or hepatitis B/C infection. Hepatitis B screening test must be performed at or in the preceding 3 months of screening visit." 5. Protocol: Clarification on reporting of laboratory abnormalities to define how they should be reported as AE, SAE or SUSAR. 6. Protocol: Clarification on exclusion criteria #24. New wording: "24. Patients currently recruited to other clinical trial(s) involving an investigational medicinal product (except any observational follow-up periods not involving an IMP)." 7. Patient Information Sheet: description of indemnity was amended 8. Patient Information Sheet: Explanation on follow up after withdrawal was made clearer 9. Protocol: US time-pointss have been amended (a total of 10 time-points remains unchanged) (taken at baseline, not week 8- visit 5) 10. SmPC: Update on SmPCs for Rituximab and Tocilizumab 11. Addition of Pre and Post Biopsy Assessment Form Other minor formatting changes, clarifications, corrections to the above documents.
    17 Jun 2015
    1. Addition of trial sites (Manchester, Bath, and Guys). 2. Change of PI at Homerton trial site (Change from Beena Hamed to Piero Reynolds)
    18 Aug 2015
    Addition of trial site (Leeds).
    15 Aug 2016
    1. Change of Sponsor Representative. 2. Change of follow-up period for some patients resulting in updates to the end of study definition, PIS and ICF. 3. Update to sample size calculation. 4. New document ‘end of trial letter’ for participants. 5. Clarifications to existing inclusion and exclusion criteria. 6. Clarification that RF/CCP tests should be conducted at screening unless the tests have been done previously and do not need repeating as per local guidelines. 7. Clarification that baseline assessments should be done within a +/- 7 day window 8. Clarification that X-rays must be performed as per routine screening for tuberculosis at screening 9. Removal of text regarding statins as patients will be managed as per routine care 10. Clarification the serum immunoglobulins must be performed at screening (unless done 8 weeks before) 11. Clarification that a patient deemed a non-responder at visit 7 (week 16) can switch treatment at their subsequent visit 12. Clarification that for visits 7 onwards a patient can switch treatment at the following visit 13. Addition of secondary endpoints 14. Other minor amendments to protocol
    30 Aug 2017
    Addition of poster for recruitment purposes Extension of recruitment period to 1st December 2017 Minor change to patient end of trial letter in line with recruitment extension Use of patient video (already approved for STRAP trial) for purposes of R4RA trial recruitment.
    18 Dec 2017
    1. Clarification on end of trial- The R4-RA trial has undergone 3 no-cost extensions therefore the trial must cease recruitment in December 2017 or when at least 86 B-cell poor and at least 51-B-cell rich patients (numbers required for 90% power) has been reached, whichever comes first. 2. Digital Image analysis added to protocol 3. Change of end of trial definition from LPLV to 6 months after the LPLV to allow time for sample processing and image analysis, if required. 4. Amendments and clarifications to study endpoints

    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.
    The study has some limitations including, uncertainty about the optimal B-cell poor/rich classification (cellular v molecular), the inclusion of an active comparator (tocilizumab) that, similarly to rituximab, modulates B cell function and survival.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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