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    Clinical Trial Results:
    Stratification of Biologic Therapies for RA by Pathobiology (STRAP-EU): A randomised, open-labelled biopsy-driven stratification trial in DMARD inadequate responder patients randomised to Etanercept, Tocilizumab or Rituximab.

    Summary
    EudraCT number
    		 2017-004079-30
    Trial protocol
    		 BE   ES   PT   IT  
    Global end of trial date
    23 Jan 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Dec 2021
    First version publication date
    16 Dec 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    STRAP_ReDA_012206
    Additional study identifiers
    ISRCTN number
    		 ISRCTN43336433
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Queen Mary University of London (QMUL)
    Sponsor organisation address
    Joint Research Management Office (JRMO), Empire House, 67-75 New Road, London, United Kingdom, E1 1HH
    Public contact
    Professor Costantino Pitzalis, Centre for Experimental Medicine and Rheumatology, QMUL, QMUL, emrclinicaltrials@qmul.ac.uk
    Scientific contact
    Professor Costantino Pitzalis, Centre for Experimental Medicine and Rheumatology, QMUL, QMUL, emrclinicaltrials@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
    23 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Jan 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main aim of this study is to test the utility of analysing synovial B cell infiltrates as a potential biomarker to guide therapeutic decisions in patients failing DMARD therapy. We hypothesise that stratification of patients according to their synovial B cell infiltrate into the B cellpoor/rich pathotype by histomorphology and/or a B cell specific gene expression module derived from FANTOM5 (Functional ANnoTation Of Mammalian Genome) will better define response rates. Specifically, we hypothesise that the other two treatment options (Tocilizumab and Etanercept, treated together for analysis) are superior to Rituximab in B-cell-poor patients. As documented in the protocol and statistical analyses plan, data from the STRAP trial will be analysed together with the data from the STRAP-EU trial (identical trial running in the EU) for all endpoints and submitted as one clinical study report at the end of the trials.
    Protection of trial subjects
    The drugs used in this trial are all 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. Injection-site reactions with Tocilizumab and Etanercept may also occur. The risk of such reactions as well as 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 experience discomfort from the local anaesthetic and biopsy procedure. However, published data on this procedure confirms that it is well tolerated, safe, 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
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    01 Jun 2015
    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
    Portugal: 3
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    United Kingdom: 184
    Worldwide total number of subjects
    223
    EEA total number of subjects
    39
    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)
    173
    From 65 to 84 years
    49
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patient with rheumatoid arthritis were recruited from rheumatology clinics at 20 sites in the United Kingdom, 3 sites in Italy, and 1 site in each of Belgium, Spain, and Portugal. Recruitment began in June 2015 and ended in May 2019.

    Pre-assignment
    Screening details
    		 294 patients provided informed consent, however only 228 of these underwent synovial biopsy. 2 were subsequently found to be inelegibile, prior to randomisation, therefore a total of 226 patients were randomised onto the trial. 3 were excluded from the ITT analyses as they received steroid injections <4 weeks prior to screening (exclusion criteria)

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    Only the joint assessor who assessed the patients swollen and tender joints at each visit was blinded to treatment. The patient and investigator were not blinded to treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 Patients randomised to Rituximab
    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
    Infusion
    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 who continues to have active disease or flares will be re-treated at 24 weeks, as per the SmPC

    Arm title
    		 Tocilizumab
    Arm description
    		 Patients randomised to tocilizumab.
    Arm type
    		 Active drug

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The recommended dose of Tocilizumab for adult patients with RA is 162mg administered as a weekly subcutaneous injection and it was self-administered by patients.

    Arm title
    		 Etanercept
    Arm description
    		 Patients randomised to Etanercept.
    Arm type
    		 Active drug

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The recommended dose of Etanercept for adult patients with RA is 50 mg (given as a subcutaneous injection) once a week and it was self-administered by patients.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Only the joint assessor who assessed the patients swollen and tender joints at each visit was blinded to treatment. The patient and investigator were not blinded to treatment.
    Number of subjects in period 1
    		Rituximab Tocilizumab Etanercept
    Started
    78
    73
    72
    Completed
    78
    73
    72
    Period 2
    Period 2 title
    Baseline to Week 16
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [2]
    Blinding implementation details
    Only the joint assessor who assessed the patients swollen and tender joints at each visit was blinded to treatment. The patient and investigator were not blinded to treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 Patients randomised to rituximab completing the period up to week 16.
    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
    Infusion
    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 who continues to have active disease or flares will be re-treated at 24 weeks, as per the SmPC

    Arm title
    		 Tocilizumab
    Arm description
    		 Patients randomised to tocilizumab and completing the period up to week 16.
    Arm type
    		 Active drug

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The recommended dose of Tocilizumab for adult patients with RA is 162mg administered as a weekly subcutaneous injection and it was self-administered by patients.

    Arm title
    		 Etanercept
    Arm description
    		 Patients randomised to etanercept and compelting the period up to week 16.
    Arm type
    		 Active drug

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The recommended dose of Etanercept for adult patients with RA is 50 mg (given as a subcutaneous injection) once a week and it was self-administered by patients.

    Notes
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Only the joint assessor who assessed the patients swollen and tender joints at each visit was blinded to treatment. The patient and investigator were not blinded to treatment.
    Number of subjects in period 2
    		Rituximab Tocilizumab Etanercept
    Started
    78
    73
    72
    Completed
    72
    72
    69
    Not completed
    6
    1
    3
         Consent withdrawn by subject
    4
    -
    -
         Adverse event, non-fatal
    2
    1
    3
    Period 3
    Period 3 title
    Week 16 to week 48
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [3]
    Blinding implementation details
    Only the joint assessor who assessed the patients swollen and tender joints at each visit was blinded to treatment. The patient and investigator were not blinded to treatment.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Rituximab
    Arm description
    		 Patients randomsied to rituximab and receiving rituximab at the start of the period week 16-48.
    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
    Infusion
    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 who continues to have active disease or flares will be re-treated at 24 weeks, as per the SmPC

    Arm title
    		 Tocilizumab
    Arm description
    		 Patients randomsied to tocilizumab and receiving tocilizumab at the start of the period week 16-48.
    Arm type
    		 Active drug

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The recommended dose of Tocilizumab for adult patients with RA is 162mg administered as a weekly subcutaneous injection and it was self-administered by patients.

    Arm title
    		 Etanercept
    Arm description
    		 Patients randomsied to etanercept and receiving etanercept at the start of the period week 16-48.
    Arm type
    		 Active drug

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The recommended dose of Etanercept for adult patients with RA is 50 mg (given as a subcutaneous injection) once a week and it was self-administered by patients.

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

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The recommended dose of Etanercept for adult patients with RA is 50 mg (given as a subcutaneous injection) once a week and it was self-administered by patients.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    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 who continues to have active disease or flares will be re-treated at 24 weeks, as per the SmPC

    Arm title
    		 Tocilizumab + Rituximab
    Arm description
    		 Patient who was randomized to Tocilizumab but switched to rituximab at week 24 (protocol deviation).
    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
    Infusion
    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 who continues to have active disease or flares will be re-treated at 24 weeks, as per the SmPC

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The recommended dose of Tocilizumab for adult patients with RA is 162mg administered as a weekly subcutaneous injection and it was self-administered by patients.

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

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The recommended dose of Etanercept for adult patients with RA is 50 mg (given as a subcutaneous injection) once a week and it was self-administered by patients.

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The recommended dose of Tocilizumab for adult patients with RA is 162mg administered as a weekly subcutaneous injection and it was self-administered by patients.

    Arm title
    		 Etanercept + Rituximab
    Arm description
    		 Patients randomised to etanercept and switched to rituximab at week 16 or later.
    Arm type
    		 Active drug

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The recommended dose of Etanercept for adult patients with RA is 50 mg (given as a subcutaneous injection) once a week and it was self-administered by patients.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    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 who continues to have active disease or flares will be re-treated at 24 weeks, as per the SmPC

    Notes
    [3] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Only the joint assessor who assessed the patients swollen and tender joints at each visit was blinded to treatment. The patient and investigator were not blinded to treatment.
    Number of subjects in period 3 [4]
    		Rituximab Tocilizumab Etanercept Rituximab + Etanercept Tocilizumab + Rituximab Tocilizumab + Etanercept Etanercept + Rituximab
    Started
    64
    62
    61
    8
    1
    10
    8
    Completed
    46
    56
    37
    17
    1
    13
    22
    Not completed
    18
    6
    24
    4
    0
    2
    1
         Consent withdrawn by subject
    3
    -
    2
    -
    -
    -
    -
         Physician decision
    2
    -
    1
    1
    -
    2
    -
         Adverse event, non-fatal
    -
    -
    5
    2
    -
    -
    1
         Transferred to other arm/group
    13
    6
    15
    -
    -
    -
    -
         Pregnancy
    -
    -
    1
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    1
    -
    -
    -
    Joined
    0
    0
    0
    13
    0
    5
    15
         Transferred in from other group/arm
    -
    -
    -
    13
    -
    5
    15
    Notes
    [4] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: The reason is due to the system not allowing the starting number of a group to be 0. The patient in Tocilizumab + Rituximab group transfered out of Tocilizumab group however I could not record them as a transfer into the Tocilizumab + Rituximab group since they are recorded in the starting number for this group. Ideally the starting number for the Tocilizumab + Rituximab group would have been 0, the completed number 1, & transfer in number 1, which would have given a net of zero transfers.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Patients randomised to Rituximab

    Reporting group title
    Tocilizumab
    Reporting group description
    		 Patients randomised to tocilizumab.

    Reporting group title
    Etanercept
    Reporting group description
    		 Patients randomised to Etanercept.

    Reporting group values
    		 Rituximab Tocilizumab Etanercept Total
    Number of subjects
    		 78 73 72 223
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 59 55 59 173
        From 65-84 years
    		 19 18 12 49
        85 years and over
    		 0 0 1 1
    Age continuous
    Units: years
        median (standard deviation)
    		 55.1 ± 13.1 53.5 ± 14.0 52.2 ± 13.1 -
    Gender categorical
    Units: Subjects
        Female
    		 60 54 54 168
        Male
    		 18 19 18 55
    Pathotype
    Units: Subjects
        Diffuse Myeloid
    		 22 18 20 60
        Lympho-Myeloid
    		 42 41 35 118
        Pauci-immune Fibroid
    		 14 12 13 39
        Myeloid–Lymphoid
    		 0 1 0 1
        Ungradable
    		 0 1 4 5
    Study (UK or EU)
    Study patient was recruited to (STRAP-UK or STRAP-EU)
    Units: Subjects
        EU
    		 14 13 12 39
        UK
    		 64 60 60 184
    Rheumatoid factor (RF) OR Anti–citrullinated protein antibody (ACPA) positive
    Units: Subjects
        negative
    		 10 14 12 36
        positive
    		 68 59 60 187
    Rheumatoid factor (RF) positive
    Units: Subjects
        negative
    		 21 25 23 69
        positive
    		 57 48 49 154
    Anti–citrullinated protein antibody (ACPA) positive
    Units: Subjects
        negative
    		 15 16 18 49
        positive
    		 61 57 54 172
        Not reported
    		 2 0 0 2
    Current methotrexate use
    Units: Subjects
        No
    		 24 26 31 81
        Yes
    		 54 47 41 142
    Current prednisolone use
    Units: Subjects
        No
    		 63 65 58 186
        Yes
    		 15 8 14 37
    Number of current DMARDs
    Units: Subjects
        None
    		 30 19 22 71
        One
    		 32 40 36 108
        Two
    		 15 13 13 41
        Three+
    		 1 1 1 3
    Alcohol consumption
    Units: Subjects
        Yes
    		 36 31 31 98
        No
    		 37 42 41 120
        Not reported
    		 5 0 0 5
    Smoking (ever)
    Units: Subjects
        Yes
    		 41 42 35 118
        No
    		 37 31 37 105
    BMI
    Units: kg/m²
        median (inter-quartile range (Q1-Q3))
    		 25.0 (22.4 to 29.5) 25.0 (22.4 to 31.1) 25.7 (23.5 to 30.5) -
    Disease duration
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 3.0 (1.0 to 8.0) 3.0 (1.0 to 8.0) 5.0 (2.0 to 8.2) -
    Clinical disease activity index (CDAI)
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 31.3 (24.6 to 41.2) 33.8 (25.9 to 41.8) 33.8 (26.0 to 44.2) -
    Erythrocyte sedimentation rate (ESR)
    Units: mm/h
        median (inter-quartile range (Q1-Q3))
    		 27.0 (16.0 to 45.8) 28.0 (15.0 to 45.0) 25.0 (16.0 to 37.0) -
    C-reactive protein (CRP)
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    		 11.5 (4.5 to 29.2) 13.0 (5.0 to 28.0) 10.0 (3.5 to 26.0) -
    Haemoglobin (Hb)
    Units: g/L
        median (inter-quartile range (Q1-Q3))
    		 123.5 (117.2 to 134.8) 113.0 (101.2 to 120.5) 125.5 (119.0 to 130.0) -
    Number of tender joints, 0-28
    Units: Score 0-28
        median (inter-quartile range (Q1-Q3))
    		 10.0 (7.0 to 17.8) 11.0 (7.0 to 19.0) 13.5 (8.0 to 20.0) -
    Number of swollen joints, 0-28
    Units: Score 0-28
        median (inter-quartile range (Q1-Q3))
    		 7.0 (4.0 to 11.0) 7.0 (5.0 to 10.0) 7.0 (4.0 to 10.2) -
    Number of tender joints (0-68)
    Units: Score 0-68
        median (inter-quartile range (Q1-Q3))
    		 17.5 (11.0 to 30.8) 16.0 (11.0 to 27.0) 20.0 (14.0 to 31.0) -
    Number of swollen joints (0-68)
    Units: Score 0-68
        median (inter-quartile range (Q1-Q3))
    		 9.0 (5.0 to 14.0) 9.0 (6.0 to 13.0) 9.0 (5.0 to 13.0) -
    VAS Patient’s global assessment—arthritis, 0–100
    Units: Score 0-100
        median (inter-quartile range (Q1-Q3))
    		 71.5 (46.2 to 84.8) 75.0 (55.0 to 89.0) 72.5 (60.8 to 87.2) -
    VAS Physician’s global assessment, 0–100
    Units: Score 0-100
        median (inter-quartile range (Q1-Q3))
    		 55.5 (38.2 to 75.5) 61.0 (46.0 to 82.0) 66.5 (45.8 to 79.2) -
    28 joint count Disease Activity Score (DAS-28), ESR
    Units: Score
        arithmetic mean (standard deviation)
    		 5.8 ± 1.3 6.0 ± 1.3 6.0 ± 0.9 -
    28 joint count Disease Activity Score (DAS-28), CRP
    Units: Score
        arithmetic mean (standard deviation)
    		 5.4 ± 1.1 5.6 ± 1.1 5.5 ± 1.0 -
    Health assessment questionnaire (HAQ) score
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 1.6 (1.0 to 2.1) 1.8 (1.2 to 2.2) 1.7 (1.1 to 2.1) -
    van der Heijde modified Sharp score (SHSS), Total
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 5.0 (2.0 to 11.0) 5.0 (1.0 to 14.8) 4.0 (0.0 to 12.0) -
    van der Heijde modified Sharp score (SHSS), Erosion
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 3.0 (0.2 to 7.0) 1.0 (0.0 to 6.0) 2.0 (0.0 to 6.0) -
    van der Heijde modified Sharp score (SHSS), Joint Space Narrowing
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 1.0 (0.0 to 6.0) 3.0 (0.0 to 11.0) 0.5 (0.0 to 6.5) -
    Ultrasound 12-max score (Power Doppler)
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 7.5 (3.8 to 12.2) 7.0 (3.0 to 11.0) 7.0 (4.0 to 11.0) -
    Ultrasound 12-max score (Synovial Thickening)
    Units: Score
        arithmetic mean (standard deviation)
    		 23.8 ± 5.7 22.7 ± 6.1 22.3 ± 6.7 -

    End points

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    End points reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Patients randomised to Rituximab

    Reporting group title
    Tocilizumab
    Reporting group description
    		 Patients randomised to tocilizumab.

    Reporting group title
    Etanercept
    Reporting group description
    		 Patients randomised to Etanercept.
    Reporting group title
    Rituximab
    Reporting group description
    		 Patients randomised to rituximab completing the period up to week 16.

    Reporting group title
    Tocilizumab
    Reporting group description
    		 Patients randomised to tocilizumab and completing the period up to week 16.

    Reporting group title
    Etanercept
    Reporting group description
    		 Patients randomised to etanercept and compelting the period up to week 16.
    Reporting group title
    Rituximab
    Reporting group description
    		 Patients randomsied to rituximab and receiving rituximab at the start of the period week 16-48.

    Reporting group title
    Tocilizumab
    Reporting group description
    		 Patients randomsied to tocilizumab and receiving tocilizumab at the start of the period week 16-48.

    Reporting group title
    Etanercept
    Reporting group description
    		 Patients randomsied to etanercept and receiving etanercept at the start of the period week 16-48.

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

    Reporting group title
    Tocilizumab + Rituximab
    Reporting group description
    		 Patient who was randomized to Tocilizumab but switched to rituximab at week 24 (protocol deviation).

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

    Reporting group title
    Etanercept + Rituximab
    Reporting group description
    		 Patients randomised to etanercept and switched to rituximab at week 16 or later.

    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 RNA-seq classification, randomised to rituximab and analysed as ITT at week 16.

    Subject analysis set title
    ITT week 16 - B cell poor - Tocilizumab/Etanercept
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subgroup of patients classified as B cell poor by RNA-seq classification, randomised to tocilizumab OR etanercept, 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 RNA-sequencing classification, randomised to rituximab, and analysed as ITT at week 16.

    Subject analysis set title
    ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subgroup of patients classified as B cell rich by RNA-sequencing classification, randomised to either tocilizumab OR etanercept, 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 RNA-seq classification, randomised to rituximab and analysed as per protocol at week 16.

    Subject analysis set title
    PP week 16 - B cell poor - Tocilizumab/Etanercept
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell poor by RNA-seq classification, randomised to tocilizumab OR etanercept, and analysed as per protocol 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 RNA-seq classification, randomised to rituximab and analysed as ITT at week 16.

    Subject analysis set title
    PP week 16 - B cell rich - Tocilizumab/Etanercept
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subgroup of patients classified as B cell rich by RNA-seq classification, randomised to tocilizumab OR etanercept, and analysed as per protocol at week 16.

    Subject analysis set title
    Week 16 - B cell poor - Rituximab - MTX
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 16 - B cell poor - Rituximab: Patients on methotrexate at baseline

    Subject analysis set title
    Week 16 - B cell poor - TOC/ETN - MTX
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 16 - B cell poor - tocilizumab or etanercept: Patients on methotrexate at baseline

    Subject analysis set title
    Week 16 - B cell poor - Rituximab - NO MTX
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 16 - B cell poor - Rituximab: Patient NOT on methotrexate at baseline

    Subject analysis set title
    Week 16 - B cell poor - TOC/ETN - NO MTX
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 16 - B cell poor - tocilizumab or etanercept: Patient NOT on methotrexate at baseline

    Subject analysis set title
    Week 16 - B cell rich - Rituximab - MTX
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 16 - B cell rich - Rituximab: Patients on methotrexte at baseline

    Subject analysis set title
    Week 16 - B cell rich - TOC/ETN - MTX
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 16 - B cell rich - tocilizumab or etanercept: Patient on methotrexate at baseline

    Subject analysis set title
    Week 16 - B cell rich - Rituximab - NO MTX
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 16 - B cell rich - rituximab: Patients not on methotrexate at baseline

    Subject analysis set title
    Week 16 - B cell rich - TOC/ETN - NO MTX
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 16 - B cell rich - tocilizumab or etanercept: Patients not on methotrexate at baseline

    Subject analysis set title
    Switchers to Rituximab - Week 16 (+16)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients deemed treatment failures at 16 weeks from baseline were switched to another therapeutic option and their response was evaluated 16 weeks after that

    Subject analysis set title
    Switchers to Etanercept - Week 16 (+16)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients deemed treatment failures at 16 weeks from baseline were switched to another therapeutic option and their response was evaluated 16 weeks after that

    Primary: ACR20

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    End point title
    		 ACR20
    End point description
    ACR20 was used to identify responders/non-responders to determine treatment switches. Participants who fulfil the following criteria are considered responders: 20% or more improvement in tender and swollen joint counts and 20% or more improvement in 3 of the 5 remaining ACR-core set measures: patient and physician global assessments (both 10 cm VAS), pain (VAS), disability as measured by HAQ, and an acute-phase reactant. Particpants who do not reach this criteria are considered non-responders.
    End point type
    Primary
    End point timeframe
    16 weeks
    End point values
    		 ITT week 16 - B cell poor - Rituximab ITT week 16 - B cell poor - Tocilizumab/Etanercept ITT week 16 - B cell rich - Rituximab ITT week 16 - B cell rich - Tocilizumab/Etanercept PP week 16 - B cell poor - Rituximab PP week 16 - B cell poor - Tocilizumab/Etanercept PP week 16 - B cell rich - Rituximab PP week 16 - B cell rich - Tocilizumab/Etanercept Week 16 - B cell poor - Rituximab - MTX Week 16 - B cell poor - TOC/ETN - MTX Week 16 - B cell poor - Rituximab - NO MTX Week 16 - B cell poor - TOC/ETN - NO MTX Week 16 - B cell rich - Rituximab - MTX Week 16 - B cell rich - TOC/ETN - MTX Week 16 - B cell rich - Rituximab - NO MTX Week 16 - B cell rich - TOC/ETN - NO MTX Switchers to Rituximab - Week 16 (+16) Switchers to Etanercept - Week 16 (+16)
    Number of subjects analysed
    41
    77
    32
    66
    35
    57
    30
    59
    28
    50
    16
    27
    26
    36
    8
    30
    24
    36
    Units: Patients
        Responder
    23
    46
    21
    49
    20
    33
    19
    43
    17
    32
    9
    14
    18
    28
    5
    21
    8
    7
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, ITT
    Statistical analysis description
    ITT week 16 - B cell poor - Rituximab v ITT week 16 - B cell poor - Tocilizumab/Etanercept
    Comparison groups
    ITT week 16 - B cell poor - Rituximab v ITT week 16 - B cell poor - Tocilizumab/Etanercept
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 2.66
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, ITT
    Statistical analysis description
    ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Comparison groups
    ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 5.07
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, PP
    Statistical analysis description
    Per protocol week 16 - B cell poor - Rituximab v Per protocol week 16 - B cell poor - Tocilizumab/Etanercept
    Comparison groups
    PP week 16 - B cell poor - Rituximab v PP week 16 - B cell poor - Tocilizumab/Etanercept
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 2.4
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, PP
    Statistical analysis description
    Per protocol week 16 - B cell rich - Rituximab v Per protocol week 16 - B cell rich - Tocilizumab/Etanercept
    Comparison groups
    PP week 16 - B cell rich - Rituximab v PP week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 4.47
    Statistical analysis title
    		 Interaction: Treatment*B cell status, ITT
    Statistical analysis description
    Analysis conducted on the whole ITT population
    Comparison groups
    ITT week 16 - B cell poor - Rituximab v ITT week 16 - B cell poor - Tocilizumab/Etanercept v ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.46
    Method
    		 Likelihood ratio test
    Confidence interval
    Notes
    [1] - Interaction test conducted through 2 nested logistic regression models
    Statistical analysis title
    		 Interaction: MTX use*Study, ITT
    Statistical analysis description
    Analysis conducted on the whole ITT cohort
    Comparison groups
    ITT week 16 - B cell poor - Rituximab v ITT week 16 - B cell poor - Tocilizumab/Etanercept v ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.96
    Method
    		 Likelihood ratio test
    Confidence interval
    Notes
    [2] - Analysis conducted through 2 nested logistic regression models
    Statistical analysis title
    		 RTX vs. TOC/ETN, B cell rich, ITT
    Comparison groups
    ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 2.06
    Statistical analysis title
    		 Meta-analysis, TOC/ETA vs. RTX, B cell poor, ITT
    Comparison groups
    ITT week 16 - B cell poor - Tocilizumab/Etanercept v ITT week 16 - B cell poor - Rituximab
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 2.14
    Notes
    [3] - A fixed-effects Mantel-Haenszel meta-analysis was performed on the two studies (STRAP and STRAP-EU) to obtain a unified adjusted odds ratio and 95% CI, as an alternative way of adjusting for site. This was carried as a repetitio of the primary analysis on the B cell POOR population.
    Statistical analysis title
    		 B poor, MTX: RTX vs TOC/ETN
    Comparison groups
    Week 16 - B cell poor - Rituximab - MTX v Week 16 - B cell poor - TOC/ETN - MTX
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 3.03
    Statistical analysis title
    		 B poor, NO MTX: RTX vs TOC/ETN
    Comparison groups
    Week 16 - B cell poor - Rituximab - NO MTX v Week 16 - B cell poor - TOC/ETN - NO MTX
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 2.85
    Statistical analysis title
    		 B rich, MTX: RTX vs TOC/ETN
    Comparison groups
    Week 16 - B cell rich - Rituximab - MTX v Week 16 - B cell rich - TOC/ETN - MTX
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 5.53
    Statistical analysis title
    		 B rich, NO MTX: RTX vs TOC/ETN
    Comparison groups
    Week 16 - B cell rich - Rituximab - NO MTX v Week 16 - B cell rich - TOC/ETN - NO MTX
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 7.88
    Statistical analysis title
    		 RTX vs. ETA - 16 weeks after treatment switch
    Comparison groups
    Switchers to Etanercept - Week 16 (+16) v Switchers to Rituximab - Week 16 (+16)
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 7.9

    Secondary: ACR50

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    End point title
    		 ACR50
    End point description
    Participants who fulfil the following criteria are considered responders according to ACR50: 50% or more improvement in tender and swollen joint counts and 50% or more improvement in 3 of the 5 remaining ACR-core set measures: patient and physician global assessments (both 10 cm VAS), pain (VAS), disability as measured by HAQ, and an acute-phase reactant.
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 ITT week 16 - B cell poor - Rituximab ITT week 16 - B cell poor - Tocilizumab/Etanercept ITT week 16 - B cell rich - Rituximab ITT week 16 - B cell rich - Tocilizumab/Etanercept PP week 16 - B cell poor - Rituximab PP week 16 - B cell poor - Tocilizumab/Etanercept PP week 16 - B cell rich - Rituximab PP week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects analysed
    41
    77
    32
    66
    35
    57
    30
    59
    Units: Patients
        Responder
    12
    35
    9
    33
    9
    25
    9
    30
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, ITT
    Statistical analysis description
    ITT week 16 - B cell poor - Rituximab v ITT week 16 - B cell poor - Tocilizumab/Etanercept
    Comparison groups
    ITT week 16 - B cell poor - Rituximab v ITT week 16 - B cell poor - Tocilizumab/Etanercept
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 5.18
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, ITT
    Statistical analysis description
    ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Comparison groups
    ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.23
         upper limit
    		 8.41
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, PP
    Statistical analysis description
    Per protocol week 16 - B cell poor - Rituximab v Per protocol week 16 - B cell poor - Tocilizumab/Etanercept
    Comparison groups
    PP week 16 - B cell poor - Rituximab v PP week 16 - B cell poor - Tocilizumab/Etanercept
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 5.94
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, PP
    Statistical analysis description
    Per protocol week 16 - B cell rich - Rituximab v Per protocol week 16 - B cell rich - Tocilizumab/Etanercept
    Comparison groups
    PP week 16 - B cell rich - Tocilizumab/Etanercept v PP week 16 - B cell rich - Rituximab
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 6.97

    Secondary: ACR70

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    End point title
    		 ACR70
    End point description
    Participants who fulfil the following criteria are considered responders according to ACR70: 70% or more improvement in tender and swollen joint counts and 70% or more improvement in 3 of the 5 remaining ACR-core set measures: patient and physician global assessments (both 10 cm VAS), pain (VAS), disability as measured by HAQ, and an acute-phase reactant.
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 ITT week 16 - B cell poor - Rituximab ITT week 16 - B cell poor - Tocilizumab/Etanercept ITT week 16 - B cell rich - Rituximab ITT week 16 - B cell rich - Tocilizumab/Etanercept PP week 16 - B cell poor - Rituximab PP week 16 - B cell poor - Tocilizumab/Etanercept PP week 16 - B cell rich - Rituximab PP week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects analysed
    41
    77
    32
    66
    35
    57
    30
    59
    Units: Patients
        Responder
    6
    18
    4
    20
    5
    13
    4
    18
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, ITT
    Statistical analysis description
    ITT week 16 - B cell poor - Rituximab v ITT week 16 - B cell poor - Tocilizumab/Etanercept
    Comparison groups
    ITT week 16 - B cell poor - Tocilizumab/Etanercept v ITT week 16 - B cell poor - Rituximab
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 5.73
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, ITT
    Statistical analysis description
    ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Comparison groups
    ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 13.89
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, PP
    Statistical analysis description
    Per protocol week 16 - B cell poor - Rituximab v Per protocol week 16 - B cell poor - Tocilizumab/Etanercept
    Comparison groups
    PP week 16 - B cell poor - Rituximab v PP week 16 - B cell poor - Tocilizumab/Etanercept
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 5.92
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, PP
    Statistical analysis description
    Per protocol week 16 - B cell rich - Rituximab v Per protocol week 16 - B cell rich - Tocilizumab/Etanercept
    Comparison groups
    PP week 16 - B cell rich - Rituximab v PP week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 10.71

    Secondary: DAS28(ESR) <= 2.6

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    End point title
    		 DAS28(ESR) <= 2.6
    End point description
    Number of patients with DAS28 (calculated using ESR) less than or equal to 2.6.
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 ITT week 16 - B cell poor - Rituximab ITT week 16 - B cell poor - Tocilizumab/Etanercept ITT week 16 - B cell rich - Rituximab ITT week 16 - B cell rich - Tocilizumab/Etanercept PP week 16 - B cell poor - Rituximab PP week 16 - B cell poor - Tocilizumab/Etanercept PP week 16 - B cell rich - Rituximab PP week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects analysed
    41
    77
    32
    66
    35
    57
    30
    59
    Units: Patients
        Responder
    6
    29
    8
    35
    6
    22
    7
    32
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, ITT
    Statistical analysis description
    ITT week 16 - B cell poor - Rituximab v ITT week 16 - B cell poor - Tocilizumab/Etanercept
    Comparison groups
    ITT week 16 - B cell poor - Rituximab v ITT week 16 - B cell poor - Tocilizumab/Etanercept
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.52
         upper limit
    		 11.17
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, ITT
    Statistical analysis description
    ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Comparison groups
    ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.2
         upper limit
    		 19.89
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, PP
    Statistical analysis description
    Per protocol week 16 - B cell poor - Rituximab v Per protocol week 16 - B cell poor - Tocilizumab/Etanercept
    Comparison groups
    PP week 16 - B cell poor - Rituximab v PP week 16 - B cell poor - Tocilizumab/Etanercept
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.13
         upper limit
    		 9.12
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, PP
    Statistical analysis description
    Per protocol week 16 - B cell rich - Rituximab v Per protocol week 16 - B cell rich - Tocilizumab/Etanercept
    Comparison groups
    PP week 16 - B cell rich - Rituximab v PP week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.79
         upper limit
    		 19.23

    Secondary: CDAI <10.1

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    End point title
    		 CDAI <10.1
    End point description
    Clinical Disease Activity Index (CDAI) score of less than 10.1
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 ITT week 16 - B cell poor - Rituximab ITT week 16 - B cell poor - Tocilizumab/Etanercept ITT week 16 - B cell rich - Rituximab ITT week 16 - B cell rich - Tocilizumab/Etanercept PP week 16 - B cell poor - Rituximab PP week 16 - B cell poor - Tocilizumab/Etanercept PP week 16 - B cell rich - Rituximab PP week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects analysed
    41
    77
    32
    66
    35
    57
    30
    59
    Units: Patients
        Responder
    16
    35
    16
    38
    14
    25
    14
    35
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, ITT
    Statistical analysis description
    ITT week 16 - rituximab - B cell poor vs ITT week 16 - tocilizumab/etanercept - B cell poor
    Comparison groups
    ITT week 16 - B cell poor - Rituximab v ITT week 16 - B cell poor - Tocilizumab/Etanercept
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 3.01
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, ITT
    Statistical analysis description
    ITT week 16 - rituximab - B cell rich vs ITT week 16 - tocilizumab/etanercept - B cell rich
    Comparison groups
    ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 4.96
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, PP
    Statistical analysis description
    Per protocol week 16 - rituximab - B cell poor vs Per protocol week 16 - tocilizumab/etanercept - B cell poor
    Comparison groups
    PP week 16 - B cell poor - Rituximab v PP week 16 - B cell poor - Tocilizumab/Etanercept
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 2.77
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, PP
    Statistical analysis description
    Per protocol week 16 - rituximab - B cell rich vs Per protocol week 16 - tocilizumab/etanercept - B cell rich
    Comparison groups
    PP week 16 - B cell rich - Rituximab v PP week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 5.31

    Secondary: CDAI

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    End point title
    		 CDAI
    End point description
    Mean % change in CDAI score at 16 weeks.
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 ITT week 16 - B cell poor - Rituximab ITT week 16 - B cell poor - Tocilizumab/Etanercept ITT week 16 - B cell rich - Rituximab ITT week 16 - B cell rich - Tocilizumab/Etanercept PP week 16 - B cell poor - Rituximab PP week 16 - B cell poor - Tocilizumab/Etanercept PP week 16 - B cell rich - Rituximab PP week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects analysed
    41
    77
    32
    66
    35
    57
    30
    59
    Units: Value
        least squares mean (confidence interval 95%)
    -18.3 (-22.9 to -13.7)
    -21.4 (-25.2 to -17.5)
    -19.6 (-23.5 to -15.7)
    -24.0 (-26.7 to -21.3)
    -18.2 (-23.1 to -13.3)
    -22.3 (-26.4 to -18.2)
    -20.1 (-24.3 to -15.9)
    -24.4 (-27.3 to -21.5)
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, ITT
    Statistical analysis description
    ITT week 16 - Rituximab - B cell poor VS ITT week 16 - tocilizumab/etanercept - B cell poor
    Comparison groups
    ITT week 16 - B cell poor - Rituximab v ITT week 16 - B cell poor - Tocilizumab/Etanercept
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 7.7
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, ITT
    Statistical analysis description
    ITT week 16 - Rituximab - B cell rich VS ITT week 16 - tocilizumab/etanercept - B cell rich
    Comparison groups
    ITT week 16 - B cell rich - Rituximab v ITT week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 8.7
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell poor, PP
    Statistical analysis description
    Per protocol week 16 - Rituximab - B cell poor VS Per protocol week 16 - tocilizumab/etanercept - B cell poor
    Comparison groups
    PP week 16 - B cell poor - Rituximab v PP week 16 - B cell poor - Tocilizumab/Etanercept
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 9.1
    Statistical analysis title
    		 RTX vs TOC/ETN, B cell rich, PP
    Statistical analysis description
    Per protocol week 16 - Rituximab - B cell rich VS Per protocol week 16 - tocilizumab/etanercept - B cell rich
    Comparison groups
    PP week 16 - B cell rich - Rituximab v PP week 16 - B cell rich - Tocilizumab/Etanercept
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were recorded from the time of the first trial specific assessment/procedure was undertaken (at the screening visit) until the end of the trial period at 48 weeks + 30 days.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Participants who received at least one dose of rituximab during the trial.

    Reporting group title
    Tocilizumab
    Reporting group description
    		 Participants who received at least one dose of tocilizumab during the trial.

    Reporting group title
    Etanercept
    Reporting group description
    		 Participants who received at least one dose of etanercept during the trial.

    Reporting group title
    No IMP
    Reporting group description
    		 Patient who did not received any IMP but experienced an SAE during particpation in the trial.

    Serious adverse events
    		 Rituximab Tocilizumab Etanercept No IMP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 99 (5.05%)
    3 / 73 (4.11%)
    9 / 107 (8.41%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of the right ovary
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture of thoracic spine
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left wrist ring finger extension tendon rupture
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Giant cell arteritis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    pacemaker insertion - elective
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Elective ovariectomy
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenic sepsis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Profound neutropenia
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial thickening
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain relating to ovarian cyst
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Appendicitis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Xanthogranulomatous cholecystitis
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute hepatitis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity pneumonitis with superadditive viral lower respiratory tract infection
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral lower respiratory tract infection, RSV +
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Pyelonephritis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right hand abscess secondary to insect bite
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza A Neutropenia
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Rituximab Tocilizumab Etanercept No IMP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    90 / 99 (90.91%)
    63 / 73 (86.30%)
    96 / 107 (89.72%)
    1 / 1 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Baker's cyst
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Genital cyst
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Malignant melanoma
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ovarian cyst NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin tags
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Blood pressure high
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Deep thrombophlebitis of the leg
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dizziness and giddiness
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    4 / 107 (3.74%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Fainting
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Giant cell arteritis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haemoptysis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemorrhage
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Hypertension arterial
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Light headedness
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nose bleed
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Post-menopausal bleeding
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Raynaud's syndrome
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rectal bleeding
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Subconjunctival hemorrhage
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Systolic hypertension
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    TIA
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vaso vagal attack
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Surgical and medical procedures
    Appendectomy
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Cataract extraction
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Cataract operation
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Cholecystectomy
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hernia repair
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hip replacement
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Knee replacement
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Knee total replacement
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ovariectomy
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pacemaker insertion (cardiac)
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Toe nail removal
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tooth extraction NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Transvaginal tape procedure
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tympanoplasty
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Administration site bruise
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Adverse drug reaction NOS
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Appetite lost
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Burning foot
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Chest pain NEC
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chronic pain
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Cyst rupture NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Drug intolerance NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Facial flushing
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    3 / 99 (3.03%)
    1 / 73 (1.37%)
    3 / 107 (2.80%)
    0 / 1 (0.00%)
         occurrences all number
    5
    1
    3
    0
    Fever
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    3 / 107 (2.80%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Flu like symptoms
         subjects affected / exposed
    6 / 99 (6.06%)
    1 / 73 (1.37%)
    7 / 107 (6.54%)
    0 / 1 (0.00%)
         occurrences all number
    6
    1
    9
    0
    Flushing
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General malaise
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hot flushes NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injection related reaction
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injection site discomfort
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injection site irritation
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Injection site lump
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injection site pain
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injection site reaction NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    8 / 107 (7.48%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    9
    0
    Injection site redness
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    4 / 107 (3.74%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Intermittent fever
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Mass NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Night sweats
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Nodule
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Other chest pain
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain aggravated
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pitting leg oedema
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Retrosternal pain
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sickness
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Swelling of feet
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Swelling of fingers
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Swelling of hands
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Swelling of legs
         subjects affected / exposed
    0 / 99 (0.00%)
    2 / 73 (2.74%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Tenderness NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tired all the time
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Tiredness
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Immune system disorders
    Hay fever
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hypersensitivity reaction
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infection induced asthma
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Uveitis NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Reproductive system and breast disorders
    Adnexal mass
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Menstrual cycle shortened
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute bronchitis
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Acute nasopharyngitis (common cold)
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Asthmatic attack
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Bronchitis NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Burning in throat
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Catarrh
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chest pain (non-cardiac)
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chest tightness
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    5 / 99 (5.05%)
    3 / 73 (4.11%)
    7 / 107 (6.54%)
    0 / 1 (0.00%)
         occurrences all number
    5
    3
    7
    0
    Difficulty breathing
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Disturbances of sensation of smell and taste
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dry cough
         subjects affected / exposed
    1 / 99 (1.01%)
    3 / 73 (4.11%)
    5 / 107 (4.67%)
    0 / 1 (0.00%)
         occurrences all number
    1
    3
    5
    0
    Dry throat
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Exacerbation of asthma
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hiccups
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hoarseness of voice
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypersensitivity pneumonitis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Itchy throat
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Laryngeal discomfort
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Loss of smell
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Nasal discharge
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasal obstruction
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain throat
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Persistent dry cough
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Phlegm
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Productive cough
         subjects affected / exposed
    3 / 99 (3.03%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Rhinorrhea
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Runny nose
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Shortness of breath
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Sore throat
         subjects affected / exposed
    8 / 99 (8.08%)
    7 / 73 (9.59%)
    4 / 107 (3.74%)
    0 / 1 (0.00%)
         occurrences all number
    8
    7
    7
    0
    Sore throat NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    2 / 73 (2.74%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Wheezes
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Crying
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Feeling down
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Feeling irritated
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Low mood
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    3 / 107 (2.80%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Memory impaired
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Panic attack
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Abnormal LFTs
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Alanine aminotransferase abnormal NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    3 / 107 (2.80%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 99 (3.03%)
    3 / 73 (4.11%)
    3 / 107 (2.80%)
    0 / 1 (0.00%)
         occurrences all number
    3
    3
    3
    0
    ALP increased
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Arthrocentesis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bilirubin elevated
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bilirubin increased
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood neutrophils abnormal
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood sugar decreased
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cholesterol high
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cholesterol levels raised
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cholesterol total increased
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Creatinine increased
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    LFTs raised
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Liver function tests abnormal NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Liver function tests raised
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lymphocyte count low
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    MCV abnormal
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neutrophil count low
         subjects affected / exposed
    2 / 99 (2.02%)
    3 / 73 (4.11%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    4
    0
    0
    Neutrophils reduced
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Platelet count low
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Raised liver enzymes
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Serum calcium
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Transaminase glutamic-pyruvic increased
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Transaminitis
         subjects affected / exposed
    0 / 99 (0.00%)
    2 / 73 (2.74%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Urine abnormal NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Urine culture positive
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vitamin D low
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight gain
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ankle sprain
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Blister rupture
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Broken elbow
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cat scratch
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fall
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Falling
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Falling down
         subjects affected / exposed
    2 / 99 (2.02%)
    4 / 73 (5.48%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    2
    7
    3
    0
    Finger injury
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fracture of anatomical neck of humerus, closed
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Golfer's elbow
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Insect bite NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Laceration of finger
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Laceration of leg
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mosquito bite
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Muscle strain
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Perforated eardrum
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash at site of injection
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin laceration
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sprain of interphalangeal (joint) of hand
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Superficial injury of hand(s) except finger(s) alone
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tooth fracture
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Wrong injection technique
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Chest tightness
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fibrillation atrial
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Heart fluttering
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Palpitation
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Palpitations
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Tachycardia NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Aura
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Faintness
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    6 / 99 (6.06%)
    4 / 73 (5.48%)
    7 / 107 (6.54%)
    0 / 1 (0.00%)
         occurrences all number
    7
    4
    7
    0
    Headache temporal
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Loss of sensation
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Migraine type headaches
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    R sciatica
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tremor of hands
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Leucopenia
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Leukopenia NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 99 (0.00%)
    6 / 73 (8.22%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    7
    1
    0
    Neutropenia aggravated
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Swollen lymph nodes
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Ear ache
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Ear disorder NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear pain
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Otitis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tinnitus
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Bloodshot eye
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Decreased night vision
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Degeneration macular
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dry eyes
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Floaters in eye
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gritty eyes
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Near vision disturbance
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Panuveitis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Red eye
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    bdomincal hernia NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Abdominal pain generalised
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Acid indigestion
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Appendicitis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blistering of mouth
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bloating
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Burning mouth syndrome
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Churning of stomach
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Dental abscess
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dental disorder NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    3 / 99 (3.03%)
    6 / 73 (8.22%)
    4 / 107 (3.74%)
    0 / 1 (0.00%)
         occurrences all number
    7
    6
    4
    0
    Diarrhoea NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    2 / 73 (2.74%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Dry mouth
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dyspepsia
         subjects affected / exposed
    1 / 99 (1.01%)
    2 / 73 (2.74%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Emesis
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Epigastric discomfort
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Epigastric pain
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gas in stomach
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastritis
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Increased stool frequency
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Loose bowel
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Loose stools
         subjects affected / exposed
    0 / 99 (0.00%)
    2 / 73 (2.74%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Lower abdominal pain
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mouth ulcer
         subjects affected / exposed
    3 / 99 (3.03%)
    5 / 73 (6.85%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    3
    6
    1
    0
    Nausea
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    3 / 107 (2.80%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Nausea alone
         subjects affected / exposed
    3 / 99 (3.03%)
    5 / 73 (6.85%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    3
    5
    2
    0
    Nausea and vomiting
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea vomiting and diarrhoea
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Oesophagitis NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oral thrush
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral ulceration
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain gum
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Stomach ache
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Stomach cramps
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Stomach discomfort
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Taste changed
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tongue erythema
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tongue ulceration
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Tooth ache
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Ulceration of mouth
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Upper abdominal pain
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vomited
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vomiting NOS
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 73 (1.37%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    2
    0
    Hepatobiliary disorders
    Hepatitis acute
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Xanthogranulomatous cholecystitis
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Actinic keratosis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Alopecia
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ankle ulcer
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bruise
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Bruise of head
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    3 / 107 (2.80%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Eczema exacerbated
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eczema NOS
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Erythema ear
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Erythema NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    4 / 107 (3.74%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Erythematous rash
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Erythematous skin rash
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Facial hair increased
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Generalised itching
         subjects affected / exposed
    1 / 99 (1.01%)
    3 / 73 (4.11%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Generalized itching
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hair loss
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Herpes simplex aggravated
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infected nail bed
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Itching papule
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Itchy
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Itchy skin
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Localised itching
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Macular rash
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Malar rash
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nail dystrophy
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nail thinning
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Numbness in leg
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Numbness in toes
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Papular rash
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Paraesthesia lower limb
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Paraesthesia skin
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Petechial rash
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Photosensitivity (NOS)
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pins and needles
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pityriasis rosea
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psoriasis aggravated
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash both legs
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Rash face
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Rash NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Rash over arms
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Red rash
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Redness
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Redness of face
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Scalp folliculitis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Shingles
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin fragility
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin lesion NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin rash
         subjects affected / exposed
    1 / 99 (1.01%)
    2 / 73 (2.74%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Skin ulcer NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin wound
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sun blister
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Swollen lips
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tendency to bruise easily
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tinea corporis
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tingling feet/hands
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Unspecified pruritic disorder
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Yeast infection of the skin
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Kidney stone
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Microscopic haematuria
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Endocrine disorders
    Type II diabetes mellitus
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Arthralgia aggravated
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Back pain
         subjects affected / exposed
    3 / 99 (3.03%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Bursitis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Calf pain
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Coccyx pain
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Coxalgia
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cramps
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cramps of extremities
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Early morning stiffness
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fibromyalgia
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Foot pain
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ganglion
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ganglion of joint
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Generalised joint pains
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Golfer's elbow
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Groin pain
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hand pain
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Joint inflammation
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Knee lock
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Knee pain
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Leg cramps
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Low back pain
         subjects affected / exposed
    3 / 99 (3.03%)
    1 / 73 (1.37%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    2
    0
    Muscle cramps
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscle fatigue
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle weakness lower limb
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Neck pain
         subjects affected / exposed
    3 / 99 (3.03%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nocturnal leg muscle cramps
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    OA hip
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Osteoarthritis shoulders
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Osteopenia
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain back
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pain in (l) shoulder
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Pain in (r) arm
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain in (r) foot
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain in (r) hip
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pain in (r) knee
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Pain in (r) shoulder
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Pain in elbow
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain in hand
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain in hip
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain in joint, site unspecified
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain in knee
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain in leg
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Painful hand
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Painful knee
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Periarticular disorder
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Plantar fasciitis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Restless legs
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rheumatoid arthritis aggravated
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rheumatoid arthritis flare up
         subjects affected / exposed
    2 / 99 (2.02%)
    4 / 73 (5.48%)
    7 / 107 (6.54%)
    0 / 1 (0.00%)
         occurrences all number
    3
    4
    10
    0
    Rheumatoid nodule
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sciatica
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    5 / 107 (4.67%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    5
    0
    Shoulder fracture
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Shoulder pain
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Stiffness
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Swan-neck deformity
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Swelling of knees
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Swelling of wrists
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Temporomandibular joint disorder NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tenderness muscle
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Thoracic spine compression fracture
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Trigger finger
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper back pain
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wrist arthropathy
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wrist pain
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tendon rupture
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Abdominal abscess NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Abdominal infection
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abscess dental
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Abscess hand
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abscess of vulva, other
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abscess on buttock
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Acute posterior ganglionitis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bladder infection NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blister infected
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Boil on face
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bronchitis NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Cellulitis of toe
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chest infection
         subjects affected / exposed
    12 / 99 (12.12%)
    5 / 73 (6.85%)
    10 / 107 (9.35%)
    0 / 1 (0.00%)
         occurrences all number
    13
    6
    10
    0
    Chlamydial proctitis
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cold
         subjects affected / exposed
    6 / 99 (6.06%)
    5 / 73 (6.85%)
    5 / 107 (4.67%)
    0 / 1 (0.00%)
         occurrences all number
    6
    6
    7
    0
    Cold sores
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Cold sores lip
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Colitis, enteritis, and gastroenteritis of presumed infectious origin
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Common cold
         subjects affected / exposed
    5 / 99 (5.05%)
    6 / 73 (8.22%)
    9 / 107 (8.41%)
    0 / 1 (0.00%)
         occurrences all number
    5
    7
    12
    0
    Conjunctivitis NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    2 / 73 (2.74%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Coronavirus infection
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Coryza
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Coryzal symptoms
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Cystitis (NOS)
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear infection
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Ear infection NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Flu
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Food poisoning
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 99 (0.00%)
    2 / 73 (2.74%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Gastroenteritis NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Groin abscess
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Head cold
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Herpes simplex
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infected bites
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infected finger
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infected thumb
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infection
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infection respiratory
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza with other manifestations
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Joint abscess
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Keratitis viral NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Labyrinthitis NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Laryngitis NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Laryngopharyngitis
         subjects affected / exposed
    0 / 99 (0.00%)
    3 / 73 (4.11%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Lower respiratory tract infection NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    2 / 73 (2.74%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    LRTI
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Nail fungal infection NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Otitis media NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Parainfluenzae virus infection NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Pilonidal cyst
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pilonidal sinus
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pneumonia NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pyelonephritis NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinitis NOS
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Rhinopharyngitis
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sepsis NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinusitis NOS
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Skin fungal infection NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin infection NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Thigh abscess
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Throat infection
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Thrush NOS
         subjects affected / exposed
    0 / 99 (0.00%)
    2 / 73 (2.74%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Thrush vaginal
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Tooth abscess
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Tooth infection
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Upper respiratory tract infection NOS
         subjects affected / exposed
    2 / 99 (2.02%)
    2 / 73 (2.74%)
    5 / 107 (4.67%)
    0 / 1 (0.00%)
         occurrences all number
    2
    3
    8
    0
    Upper respiratory tract infection viral NOS
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Urinary tract infection NOS
         subjects affected / exposed
    2 / 99 (2.02%)
    3 / 73 (4.11%)
    6 / 107 (5.61%)
    0 / 1 (0.00%)
         occurrences all number
    3
    3
    8
    0
    URTI (upper respiratory tract infection)
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 73 (1.37%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    2
    0
    UTI
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    2 / 107 (1.87%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    5
    0
    Vaginal candida
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vaginal candidiasis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Viral infection NOS
         subjects affected / exposed
    4 / 99 (4.04%)
    1 / 73 (1.37%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    4
    1
    2
    0
    Viral pharyngitis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Whooping cough
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Wound infection NEC
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Metabolism and nutrition disorders
    Food intolerance
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypercholesterolemia
         subjects affected / exposed
    0 / 99 (0.00%)
    2 / 73 (2.74%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hypertriglyceridemia
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Iron deficiency
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 73 (0.00%)
    1 / 107 (0.93%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lipoatrophy
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 73 (1.37%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain in (l) hip
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    3 / 99 (3.03%)
    0 / 73 (0.00%)
    0 / 107 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Dec 2015
    1. Queen Mary University of London has a new appointed Sponsor representative. 2. Addition of optional MRI scans (applicable only for patients at Barts Health Trust and Leeds Teaching Hospitals NHS Trust) for a sub-set of the main study (minimum 60, maximum 90). 3. Additional post-treatment study/call at week 54-56 to record AEs/SAEs after the trial treatment period (0-48 weeks) 4. Clarifications to existing inclusion/exclusion criteria 5. Additional pre- and post- biopsy assessment forms at visits: at visit 2 (week -3 - -1) and visit 3 and at week 16 biopsy (if done) at visit 7 (week 16) and visit 8 (week 20). 6. Clarification/expansion of safety reporting requirements (incl. pregnancy) to IMP providers (Roche/Pfizer) in line with contractual agreements. 7. Creation of additional optional MRI scans combined PIS and ICF. 8. Additional study specific time point at Visit 10 (week 28) in line with planned peripheral blood analyses. 9. Amendment to Main study PIS 10. Additional secondary endpoint efficacy analysis endpoint added in line with Statistical Analysis Plan 11. Other changes to the protocol deemed minor
    27 Feb 2017
    Addition of two more inclusion criteria: Patients must have a minimum of 3 swollen joints – the joint selected for biopsy and a minimum of 2 from 28 joint count set, as assessed at biopsy visit AND selected joint for biopsy must be minimum grade 2 synovial thickening, as assessed at the biopsy visit. Other non-substantial changes.
    05 Mar 2018
    Changes to protocol: • Change of Sponsor representative to Dr Mays Jawad • Update to Statistician’s address and job role • Page 7, 34 and 85- addition that recruitment targets will be combined for STRAP and STRAP-EU trials. • Page 44-added sentence to refer to current Rituximab SmPC for shelf life of prepared infusion solution of Rituximab. • Page 49- Clarification that a translator must be made available for non-English speaking, potential STRAP participants. This should be clearly documented in the patient notes • Page 84- removal of requirement for Sponsor to send line listings of all AEs to Roche. • Page 87- Added that data from the STRAP and STRAP-EU trials will be analysed together for all endpoints and combined and submitted as one clinical study report at the end of the trial (both EudraCT numbers will be referenced in the report). • Page 91- the DMEC will review both STRAP and STRAP-EU data. • Removal of reference to R4RA trial as this has now finished recruitment (patients were previously able to go on to the R4RA trial if they were a non-responder to etanercept at week 16). Also: -SmPCs have recently been updated and submitted with this amendment - Addition of one new Trust within the UK (NHS Lothian Trust).
    27 Nov 2018
    1. Change of follow up period from 48 weeks to 24 weeks for patients recruited from January 2019 onwards. 2. Minor correction to sample size 3. GDPR updates to patient information sheet 4. Other minor corrections/clarifications to the PIS, consent form and end of trial letter 5. Update to sponsor e-mail address
    13 Mar 2020
    • Integration of RNA-seq molecular analysis into the original biopsy histopathology classification method • 4 exploratory endpoints (week 16 timepoint) moved to secondary endpoints • Modification to exploratory endpoints • Removal of RAMRIQ analysis • Roche has changed the legal representation from UK to Germany. The Marketing Authorization Holder has been changed from Roche Registration Ltd. Welwyn UK to Roche Registration GmbH (RRG), Grenzach, Germany. • The end of study definition changed from 6 months to 12 months after LPLV. • Reference Safety Information has been updated for Etanercept and Tocilizumab

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

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