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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

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    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
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 109
    Country: Number of subjects enrolled
    Belgium: 26
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Portugal: 9
    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

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    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
         Adverse event, non-fatal
    1
    5
         Consent withdrawn by subject
    -
    1
    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
         Intermittent Illness
    -
    2
    1
    -
         Transferred to other arm/group
    12
    11
    -
    -
         Pregnancy
    -
    1
    -
    -
         Adverse event, serious fatal
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    -
    4
         Consent withdrawn by subject
    1
    2
    2
    3
         Lost to follow-up
    -
    -
    -
    1
    Joined
    0
    0
    12
    11
         Transferred in from other group/arm
    -
    -
    12
    11

    Baseline characteristics

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    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