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    Clinical Trial Results:
    An international, open label, randomised controlled trial comparing rituximab with azathioprine as maintenance therapy in relapsing ANCA-associated vasculitis.

    Summary
    EudraCT number
    2012-001102-14
    Trial protocol
    GB   CZ   ES   SE   IT   IE  
    Global end of trial date
    29 Nov 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Jul 2021
    First version publication date
    09 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Ritazarem
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01697267
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Cambridge University Hospitals NHS Foundation Trust
    Sponsor organisation address
    Hills Road, Cambridge, United Kingdom, CB2 0QQ
    Public contact
    Carrie Bayliss, Cambridge University Hospitals NHS Foundation Trust, 0044 01223 348158, cctu@addenbrookes.nhs.uk
    Scientific contact
    Carrie Bayliss, Cambridge University Hospitals NHS Foundation Trust, 0044 01223 348158, cctu@addenbrookes.nhs.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
    18 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Nov 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of rituximab against azathioprine in the prevention of disease flare in ANCA-associated vasculitis patients with relapsing disease.
    Protection of trial subjects
    Trial subjects were carefully monitored for the duration of the study, with frequent visits and follow-up. Treatment administration was in line with their usual standard of care and no additional distress was expected from participation in the trial.
    Background therapy
    -
    Evidence for comparator
    Rationale for the use of rituximab in AAV: B cells play a key role in the pathogenesis of AAV. Not only are they the precursors of ANCA secreting plasma cells, but they also act as antigen presenting cells for autoreactive T cells, providing co-stimulatory support and initiating T cell activation, as well as producing pro-inflammatory cytokines, such as IL-6 and TNFα. Specifically depleting B cells with targeted biological agents, such as rituximab, is therefore a promising approach to the treatment of AAV.
    Actual start date of recruitment
    19 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Canada: 28
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United Kingdom: 86
    Country: Number of subjects enrolled
    United States: 52
    Worldwide total number of subjects
    188
    EEA total number of subjects
    6
    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)
    118
    From 65 to 84 years
    69
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    RITAZAREM is a joint venture of the European Vasculitis Study Group (EUVAS) and the Vasculitis Clinical Research Consortium (VCRC). RITAZAREM was conducted in multiple centres internationally including Europe, North America and Australia/New Zealand and Japan.

    Pre-assignment
    Screening details
    Patients were evaluated by their local trial investigators to ensure they met all the inclusion criteria and none of the exclusion criteria. The screening visit required confirmation of the diagnosis of AAV (ANCA positivity, current or historical and pertinent histology results) and documentation of organ manifestations of active AAV.

    Period 1
    Period 1 title
    Induction Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    This is an open label study. A non-blinded, open label study was been chosen for reasons of simplicity and practicality in view of RITAZAREM being an international multi-centre trial. Previous EUVAS studies with similar end-points have also been unblinded yet have led to robust and reproducible conclusions.

    Arms
    Arm title
    Rituximab induction therapy
    Arm description
    Patients were recruited at the time of relapse. All received rituximab 375 mg/m2/week x 4 and glucocorticoids to achieve remission. Those patients that achieved disease control (BVAS/WG ≤ 1 and daily prednisone dose ≤ 10 mg) by month 4 were eligible for the subsequent phase of the trial (phase 2) where they were randomised to either rituximab or control remission maintenance therapy.
    Arm type
    Induction therapy

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera, Rituxan
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were recruited at the time of relapse. All received rituximab 375 mg/m2/week x 4 doses and glucocorticoids. The first dose of rituximab should have been given within 14 days of enrolment into the trial. All induction doses of rituximab should have been completed by week 6. First infusion: the recommended initial infusion rate for rituximab is 50 mg/h; subsequently, the rate can be escalated in 50 mg/h increments every 30 minutes to a maximum of 400 mg/h. Subsequent infusions: subsequent infusions of rituximab can be started at a rate of 100 mg/h and increased by 100 mg/h increments every 30 minutes to a maximum of 400 mg/h. Pre-medication with 100 mg IV methylprednisolone will be administered prior the first infusion to minimise infusion reactions. Sites will follow local pre-medication practice for infusions 2, 3, and 4. 100 mg IV methylprednisolone will be administered prior to each maintenance dose.

    Number of subjects in period 1
    Rituximab induction therapy
    Started
    188
    Completed
    170
    Not completed
    18
         Not eligible for induction therapy
    1
         Missed randomisation window
    1
         Physician decision
    2
         Adverse event, serious fatal
    4
         Not in remission at month 4
    6
         Consent withdrawn by subject
    3
         Lost to follow-up
    1
    Period 2
    Period 2 title
    Maintenance Phase
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This is an open label study. A non-blinded, open label study has been chosen for reasons of simplicity and practicality in view of RITAZAREM being an international multi-centre trial. Previous EUVAS studies with similar end-points have also been unblinded yet have led to robust and reproducible conclusions.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Rituximab
    Arm description
    Rituximab maintenance tharapy
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera, Rituxan
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids.

    Arm title
    Azathioprine
    Arm description
    Control maintenance therapy
    Arm type
    Active comparator

    Investigational medicinal product name
    Azathioprine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients randomised to the control arm will receive oral azathioprine, to be taken daily. The maximum daily dose allowed is 200mg. The maximum treatment period is 27 months, with tapering at month 24 as described below. The target dose is 2mg/kg. The maximum daily dose is 200mg. This should be continued until month 24. The dose should then be reduced by 50% and azathioprine completely withdrawn at month 27. The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg. Methotrexate or mycophenolate mofetil were permitted for those individuals intolerant of azathioprine. Methotrexate 25 mg/week will be substituted for patients with GFR > 50 ml/min and intolerant of azathioprine even at a reduced dose of 1 mg/kg/day. Mycophenolate mofetil 2 g/day will be substituted for patients intolerant of azathioprine and with GFR < 50 ml/min, and glucocorticoids. Intolerance is defined as the occurrence of an adverse event.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The protocol comprises an induction phase (period 1) and a maintenance phase (period 2). During the induction period, all patients receive the same treatment to bring the disease under remission, only the patients who achieve remission by month 4 are entered in the randomised second phase of the trial, which aims to assess the efficacy of rituximab compared to azathioprine in the prevention of disease relapse in AAV patients with relapsing disease.
    Number of subjects in period 2 [2]
    Rituximab Azathioprine
    Started
    85
    85
    Month 24
    78
    78
    Completed
    71
    70
    Not completed
    14
    15
         Physician decision
    -
    4
         Adverse event, serious fatal
    3
    1
         Adverse event, non-fatal
    2
    2
         Consent withdrawn by subject
    5
    5
         Lost to follow-up
    4
    3
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The total number of patients enrolled in the trial comprises all patients enrolled in the induction phase of the trial (phase 1) while only those who achieved disease remission by month 4 are entered in the randomisad maintenance phase of the trial (phase 2). Baseline is taken to be at the point of randomisation (month 4) and encompass only those patients who achieve disease remission by month 4.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    Rituximab maintenance tharapy

    Reporting group title
    Azathioprine
    Reporting group description
    Control maintenance therapy

    Reporting group values
    Rituximab Azathioprine Total
    Number of subjects
    85 85 170
    Age categorical
    Age at baseline
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    54 51 105
        From 65-84 years
    30 34 64
        85 years and over
    1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.1 ± 15.1 58.6 ± 13.9 -
    Gender categorical
    Units: Subjects
        Female
    42 44 86
        Male
    43 41 84
    Race
    Units: Subjects
        White
    78 77 155
        Black
    0 0 0
        Asian
    5 5 10
        Hispanic
    2 1 3
        Other
    0 2 2
    Induction regimen
    Glucocorticoids during the induction phase. Selected prednisone induction regimen (1A or 1B). Induction Schedule A: 1 mg/kg. Induction Schedule B: 0.5 mg/kg.
    Units: Subjects
        1A
    24 24 48
        1B
    61 61 122
    ANCA type
    Units: Subjects
        anti-PR3
    61 62 123
        anti-MPO
    24 23 47
    Relapse type
    Units: Subjects
        Severe
    52 54 106
        Non-severe
    33 31 64
    Historical ANCA positivity
    Historical positivity to anti-PR3 and/or anti-MPO as declared at enrolment.
    Units: Subjects
        anti-MPO
    23 22 45
        anti-PR3
    61 61 122
        Both
    0 2 2
        Neither
    1 0 1
    Comorbidities: Hypertension
    Units: Subjects
        Yes
    41 45 86
        No
    44 40 84
        Unknwon
    0 0 0
    Comorbidities: Ischemic Heart Disease (IHD)
    Units: Subjects
        Yes
    7 1 8
        No
    78 83 161
        Unknown
    0 1 1
    Comorbidities: Chronic Lung Disease (COPD)
    Units: Subjects
        Yes
    11 13 24
        No
    74 72 146
        Unknown
    0 0 0
    Comorbidities: Cerebro-Vascular Disease (CVD)
    Units: Subjects
        Yes
    3 2 5
        No
    82 83 165
        Unknown
    0 0 0
    Comorbidities: Cancer
    Units: Subjects
        Yes
    12 7 19
        No
    73 78 151
        Unknown
    0 0 0
    Comorbidities: Venus Thromboembolism
    Units: Subjects
        Yes
    10 10 20
        No
    75 75 150
        Unknown
    0 0 0
    Comorbidities: Diabetes
    Units: Subjects
        Yes
    6 13 19
        No
    78 72 150
        Unknown
    1 0 1
    Historical Organ Involvement: Constitutional Symptom
    Units: Subjects
        Yes
    43 48 91
        No
    42 37 79
    Historical Organ Involvement: Joints
    Units: Subjects
        Yes
    58 67 125
        No
    27 18 45
    Historical Organ Involvement: Skin
    Units: Subjects
        Yes
    27 27 54
        No
    58 58 116
    Historical Organ Involvement: Mucous Membranes/Eyes
    Units: Subjects
        Yes
    28 30 58
        No
    57 55 112
    Historical Organ Involvement: Ear/Nose/Throat
    Units: Subjects
        Yes
    67 60 127
        No
    18 25 43
    Historical Organ Involvement: Heart
    Units: Subjects
        Yes
    3 3 6
        No
    82 82 164
    Historical Organ Involvement: Gastrointestinal Tract
    Units: Subjects
        Yes
    1 2 3
        No
    84 83 167
    Historical Organ Involvement: Lungs
    Units: Subjects
        Yes
    52 51 103
        No
    33 34 67
    Historical Organ Involvement: Kidneys
    Units: Subjects
        Yes
    57 57 114
        No
    28 28 56
    Historical Organ Involvement: Nervous System
    Units: Subjects
        Yes
    27 20 47
        No
    58 65 123
    Historical Organ Involvement: Other
    Units: Subjects
        Yes
    18 22 40
        No
    67 63 130
    Total number of Body Systems
    Units: Subjects
        One (1)
    3 4 7
        Two (2)
    7 9 16
        Three (3)
    12 12 24
        Four (4)
    20 11 31
        Five (5)
    18 23 41
        Six (6)
    14 16 30
        Seven (7)
    7 8 15
        Eight (8)
    2 1 3
        Nine (9)
    1 0 1
        Ten (10)
    0 1 1
        Zero (0)
    1 0 1
    Prior Treatments: Methylprednisolone
    Units: Subjects
        Yes
    63 64 127
        No
    22 21 43
    Prior Treatments: Predniso(lo)ne
    Units: Subjects
        Yes
    83 85 168
        No
    2 0 2
    Prior Treatments: Oral Cyclophosphamide
    Units: Subjects
        Yes
    32 34 66
        No
    53 51 104
    Prior Treatments: IV Cyclophosphamide
    Units: Subjects
        Yes
    41 43 84
        No
    44 42 86
    Prior Treatments: Cyclophosphamide (any)
    Units: Subjects
        Yes
    67 66 133
        No
    18 19 37
    Prior Treatments: Rituximab
    Units: Subjects
        Yes
    33 27 60
        No
    52 58 110
    Prior Treatments: Azathioprine
    Units: Subjects
        Yes
    66 60 126
        No
    19 25 44
    Prior Treatments: Methotrexate
    Units: Subjects
        Yes
    32 24 56
        No
    53 61 114
    Prior Treatments: Mycophenolate Mofetil
    Units: Subjects
        Yes
    21 22 43
        No
    64 63 127
    Prior Treatments: Sulfamethoxazole/Trimethoprim
    Units: Subjects
        Yes
    32 31 63
        No
    53 54 107
    Prior Treatments: Plasma Exchange
    Units: Subjects
        Yes
    13 11 24
        No
    72 74 146
    Prior Treatments: IVIG
    Units: Subjects
        Yes
    2 3 5
        No
    83 82 165
    Prior Treatments: anti-TNFs
    Units: Subjects
        Yes
    0 2 2
        No
    85 83 168
    Prior Treatments: Other immunosuppression
    Units: Subjects
        Yes
    4 6 10
        No
    81 79 160
    Number of prior immunosuppressants (excluding glucocorticoids)
    A count of the number of prior immunosuppressants (excluding glucocorticoids) received by each subject. The following treatments are included: cyclophosphamide (Oral or IV), rituximab, azathioprine, methotrexate, mycophenolate mefotil, IVIG, anti-TNFs, and other immunosuppression listed in the Baseline Medical History Form. In incomplete cases, the subject will be regarded as not having received the treatment specified.
    Units: Subjects
        Zero (0)
    0 0 0
        One (1)
    11 11 22
        Two (2)
    32 43 75
        Three (3)
    25 17 42
        Four (4)
    12 10 22
        Five (5)
    2 2 4
        Six (6)
    3 1 4
        Seven (7)
    0 0 0
        Eight (8)
    0 0 0
        Nine (9)
    0 1 1
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    86.6 ± 23.9 86 ± 25.3 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    171 ± 11 170 ± 9.95 -
    Body Surface Area
    Units: m2
        arithmetic mean (standard deviation)
    1.98 ± 0.278 1.96 ± 0.275 -
    Rituximab induction dose (mg/infusion)
    Units: mg
        arithmetic mean (standard deviation)
    743 ± 104.1 734 ± 101.9 -
    Disease duration
    Prior disease duration (years) - calculated from the date of diagnosis to the date of screening.
    Units: years
        arithmetic mean (standard deviation)
    7.38 ± 6.94 6.93 ± 6.10 -
    Total number of Body Systems affected
    The total count of organ manifestations reported in the Baseline Medical History Form (max count = 11), the organ systems are: Constitutional Symptom, Joints, Skin, Mucous Membranes/Eyes, Ear/Nose/Throat, Heart, Gastrointestinal Tract, Lungs, Kidneys, Nervous System, Other.
    Units: counts
        arithmetic mean (standard deviation)
    4.48 ± 1.75 4.55 ± 1.79 -
    Prior Treatments (Doses): Rituximab
    Units: gram(s)
        arithmetic mean (standard deviation)
    4466 ± 2945 5403 ± 3573 -
    Prior Treatments (Doses): Oral Cyclophosphamide
    Units: gram(s)
        arithmetic mean (standard deviation)
    46.9 ± 70.8 41.3 ± 42.3 -
    Prior Treatments (Doses): IV Cyclophosphamide
    Units: gram(s)
        arithmetic mean (standard deviation)
    7.28 ± 6.12 9.05 ± 8.42 -
    Prior Treatments (Doses): Total Cyclophosphamide
    Units: gram(s)
        arithmetic mean (standard deviation)
    24.4 ± 50.4 26.9 ± 35.5 -
    Number of prior immunosuppressants (excluding glucocorticoids)
    A count of the number of prior immunosuppressants (excluding glucocorticoids) received by each subject. The following treatments are included: cyclophosphamide (Oral or IV), rituximab, azathioprine, methotrexate, mycophenolate mefotil, IVIG, anti-TNFs, and other immunosuppression listed in the Baseline Medical History Form. In incomplete cases, the subject will be regarded as not having received the treatment specified.
    Units: subjects
        arithmetic mean (standard deviation)
    2.66 ± 1.16 2.51 ± 1.24 -

    End points

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    End points reporting groups
    Reporting group title
    Rituximab induction therapy
    Reporting group description
    Patients were recruited at the time of relapse. All received rituximab 375 mg/m2/week x 4 and glucocorticoids to achieve remission. Those patients that achieved disease control (BVAS/WG ≤ 1 and daily prednisone dose ≤ 10 mg) by month 4 were eligible for the subsequent phase of the trial (phase 2) where they were randomised to either rituximab or control remission maintenance therapy.
    Reporting group title
    Rituximab
    Reporting group description
    Rituximab maintenance tharapy

    Reporting group title
    Azathioprine
    Reporting group description
    Control maintenance therapy

    Subject analysis set title
    Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population comprises all consented subjects enrolled in the trial, regardless of whether they achieved remission and were randomised at month 4. The treatment group will be analysed as randomised (rituximab or azathioprine), patients who were enrolled but not randomised will be classified as belonging to the induction group (induction).

    Subject analysis set title
    Maintenance compliant
    Subject analysis set type
    Per protocol
    Subject analysis set description
    This per-protocol populations includes all randomised patients who have not deviated from protocolised treatment during the maintenance phase of the trial (from randomisation to month 24). Patients who withdraw from trial or from protocolised treatment will be assessed for compliance up to the point of their withdrawal.

    Subject analysis set title
    Follow-up compliant
    Subject analysis set type
    Per protocol
    Subject analysis set description
    This per-protocol populations includes all randomised patients who have not deviated from protocolised treatment during the follow-up (from randomisation to end of trial). It is assumed that maintenance compliance is necessary for follow-up compliance. Patients who withdraw from trial or from protocolised treatment will be assessed for compliance up to the point of their withdrawal.

    Primary: First Major or Minor Relapse

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    End point title
    First Major or Minor Relapse
    End point description
    The primary efficacy outcome measure of the trial is relapse-free survival, where a relapse is either major or minor. The primary analysis is a Cox regression model adjusted for the stratification factors (ANCA type, relapse severity and prednisone induction regimen) for the difference in the distribution of relapse-free survival between the rituximab arm and the azathioprine (control) arm (two-sided at α-level of 5%). Assuming a proportional hazard holds, the hazard ratio together with the 95% confidence interval will be estimated using a Cox regression model adjusted for the stratification factors.
    End point type
    Primary
    End point timeframe
    Patients are followed up from a mimumum of 36 months to a maximum of 48 months from enrolment (month 0). The primary endpoint is time to disease relapse (either minor or major relapse) from randomisation (month 4).
    End point values
    Rituximab Azathioprine Maintenance compliant Follow-up compliant
    Number of subjects analysed
    85
    85
    159
    145
    Units: subjects
    38
    60
    94
    79
    Attachments
    by Treatment and Induction Regimen
    First Major or Minor Relapse - Kaplan-Meier Plot
    by Treatment and ANCA status
    by Treatment and Relapse Type
    Hazard Ratios
    Statistical analysis title
    Cox regression model (all time points)
    Statistical analysis description
    A Cox regression model adjusted for the stratification factors (ANCA type, relapse severity and prednisone induction regimen) for the difference in the distribution of relapse-free survival between the rituximab arm and the azathioprine (control) arm (two-sided at α-level of 5%).
    Comparison groups
    Rituximab v Azathioprine
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    0.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.21
    Statistical analysis title
    Cox regression model (during treatment)
    Statistical analysis description
    There will be a closed testing procedure, first the null hypothesis will be teste for a hazard ratio of 1 at all time points. If this is rejected at a 5% level then two further sub-hypothesis will be examined using time-varying covariates: 1. A hazard ratio of 1 up to 20 months post-randomisation (i.e. during treatment). 2. A hazard ratio of 1 after 20 months post-randomisation (i.e. post treatment).
    Comparison groups
    Rituximab v Azathioprine
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.001 [2]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    0.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Notes
    [1] - Following the closed testing procedure this analysis is carried out because the null hypothesis at all time points has been rejected at 5% level.
    [2] - 1. A hazard ratio of 1 up to 20 months post-randomisation (i.e. during treatment).
    Statistical analysis title
    Cox regression model (post treatment)
    Statistical analysis description
    There will be a closed testing procedure, first the null hypothesis will be teste for a hazard ratio of 1 at all time points. If this is rejected at a 5% level then two further sub-hypothesis will be examined using time-varying covariates: 1. A hazard ratio of 1 up to 20 months post-randomisation (i.e. during treatment). 2. A hazard ratio of 1 after 20 months post-randomisation (i.e. post treatment).
    Comparison groups
    Rituximab v Azathioprine
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.004 [4]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.26
         upper limit
    0.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28
    Notes
    [3] - Following the closed testing procedure this analysis is carried out because the previous null hypothesis at all time points and during treatment have been rejected at 5% level.
    [4] - 2. A hazard ratio of 1 after 20 months post-randomisation (i.e. post treatment)

    Secondary: Major or Second Minor Relapse

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    End point title
    Major or Second Minor Relapse
    End point description
    Time to a major or second minor relapse.
    End point type
    Secondary
    End point timeframe
    Patients are followed up from a mimumum of 36 months to a maximum of 48 months from enrolment (month 0). The primary endpoint is time to disease relapse (either minor or major relapse) from randomisation (month 4).
    End point values
    Rituximab Azathioprine
    Number of subjects analysed
    85
    85
    Units: subjects
    16
    40
    Attachments
    Major or Second Minor Relapse - Kaplan-Meier Plot
    Cox Proportional Hazards Model
    Statistical analysis title
    Cox regression model (all time points)
    Statistical analysis description
    A Cox regression model adjusted for the stratification factors (ANCA type, relapse severity and prednisone induction regimen) for the difference in the distribution of relapse-free survival between the rituximab arm and the azathioprine (control) arm (two-sided at α-level of 5%).
    Comparison groups
    Rituximab v Azathioprine
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    0.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Statistical analysis title
    Cox regression model (during treatment)
    Statistical analysis description
    There will be a closed testing procedure, first the null hypothesis will be teste for a hazard ratio of 1 at all time points. If this is rejected at a 5% level then two further sub-hypothesis will be examined using time-varying covariates: 1. A hazard ratio of 1 up to 20 months post-randomisation (i.e. during treatment). 2. A hazard ratio of 1 after 20 months post-randomisation (i.e. post treatment).
    Comparison groups
    Rituximab v Azathioprine
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.008 [6]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.11
         upper limit
    0.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47
    Notes
    [5] - Following the closed testing procedure this analysis is carried out because the null hypothesis at all time points has been rejected at 5% level.
    [6] - 1. A hazard ratio of 1 up to 20 months post-randomisation (i.e. during treatment).
    Statistical analysis title
    Copy of Cox regression model (post treatment)
    Statistical analysis description
    There will be a closed testing procedure, first the null hypothesis will be teste for a hazard ratio of 1 at all time points. If this is rejected at a 5% level then two further sub-hypothesis will be examined using time-varying covariates: 1. A hazard ratio of 1 up to 20 months post-randomisation (i.e. during treatment). 2. A hazard ratio of 1 after 20 months post-randomisation (i.e. post treatment).
    Comparison groups
    Rituximab v Azathioprine
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.006 [8]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.16
         upper limit
    0.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.38
    Notes
    [7] - Following the closed testing procedure this analysis is carried out because the previous null hypotheses at all time points and during treatment have been rejected at 5% level.
    [8] - 2. A hazard ratio of 1 after 20 months post-randomisation (i.e. post treatment)

    Other pre-specified: Remission at month 4

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    End point title
    Remission at month 4
    End point description
    This analysis will report on the four month open-label induction phase of the trial. It will address the efficacy of rituximab at re-inducing remission in patients with ANCA-associated vasculitis who have relapsed.
    End point type
    Other pre-specified
    End point timeframe
    The induction phase of the trial covers the first four month, from enrolment to month 4 inclusive. In this period all patients receive the same treatment (rituximab induction therapy) aimed at re-introducing remission.
    End point values
    Rituximab induction therapy
    Number of subjects analysed
    188
    Units: subjects
        In remission
    171
        Not in remission
    17
    Attachments
    BVAS/WG - Disease Status
    No statistical analyses for this end point

    Post-hoc: Major Relapse

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    End point title
    Major Relapse
    End point description
    Time to a major relapse.
    End point type
    Post-hoc
    End point timeframe
    Patients are followed up from a mimumum of 36 months to a maximum of 48 months from enrolment (month 0). The primary endpoint is time to disease relapse (either minor or major relapse) from randomisation (month 4).
    End point values
    Rituximab Azathioprine
    Number of subjects analysed
    85
    85
    Units: subjects
    11
    26
    Attachments
    Kaplan-Meier Plot - Major Relapse
    Cox Proportional Hazards Model - Forest Plot
    Statistical analysis title
    Cox regression model (all time points)
    Statistical analysis description
    A Cox regression model adjusted for the stratification factors (ANCA type, relapse severity and prednisone induction regimen) for the difference in the distribution of relapse-free survival between the rituximab arm and the azathioprine (control) arm (two-sided at α-level of 5%).
    Comparison groups
    Rituximab v Azathioprine
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    0.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.36

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs recorded from enrollment until the end of the trial, thus events reported both during the induction and maintenance phase of the trial are reported. Reporting groups (Induction, Rituximab, Azathioprine) refer to the patient's assigned treatment group.
    Adverse event reporting additional description
    In addition to all SAEs, the following selected adverse events are reported: infections (all episodes requiring IV treatment or oral antibiotics); AEs resulting in a change in dose of trial IMPs, or the addition of relevant concomitant medication, or the occurrance of a lab abnormality; new malignancies.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    -

    Reporting group title
    Induction
    Reporting group description
    -

    Reporting group title
    Azathioprine
    Reporting group description
    -

    Serious adverse events
    Rituximab Induction Azathioprine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    43 / 85 (50.59%)
    11 / 18 (61.11%)
    48 / 85 (56.47%)
         number of deaths (all causes)
    3
    5
    1
         number of deaths resulting from adverse events
    3
    5
    1
    Vascular disorders
    Aortic dissection
    Additional description: Aortic dissection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
    Additional description: Deep vein thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 85 (4.71%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
    Additional description: Epistaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
    Additional description: Haemoptysis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
    Additional description: Haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
    Additional description: Orthostatic hypotension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    Additional description: Pulmonary embolism
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    3 / 85 (3.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular injury
    Additional description: Vascular injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
    Additional description: Vascular pseudoaneurysm
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Aortic valve replacement
    Additional description: Aortic valve replacement
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bunion operation
    Additional description: Bunion operation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac ablation
    Additional description: Cardiac ablation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystectomy
    Additional description: Cholecystectomy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colostomy closure
    Additional description: Colostomy closure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colporrhaphy
    Additional description: Colporrhaphy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dacryocystorhinostomy
    Additional description: Dacryocystorhinostomy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip arthroplasty
    Additional description: Hip arthroplasty
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    3 / 85 (3.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion
    Additional description: Infusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint resurfacing surgery
    Additional description: Joint resurfacing surgery
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Knee arthroplasty
    Additional description: Knee arthroplasty
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung lobectomy
    Additional description: Lung lobectomy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and pancreas transplant
    Additional description: Renal and pancreas transplant
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal transplant
    Additional description: Renal transplant
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sigmoidectomy
    Additional description: Sigmoidectomy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal resection
    Additional description: Small intestinal resection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal decompression
    Additional description: Spinal decompression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroidectomy
    Additional description: Thyroidectomy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular anastomosis
    Additional description: Vascular anastomosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anal squamous cell carcinoma
    Additional description: Anal squamous cell carcinoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    B-cell lymphoma
    Additional description: B-cell lymphoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bladder papilloma
    Additional description: Bladder papilloma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon neoplasm
    Additional description: Colon neoplasm
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
    Additional description: Lung adenocarcinoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
    Additional description: Pancreatic carcinoma metastatic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Pancreatic carcinoma
    Additional description: Pancreatic carcinoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sarcoma of skin
    Additional description: Sarcoma of skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
    Additional description: Squamous cell carcinoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
    Additional description: Drug hypersensitivity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
    Additional description: Hypersensitivity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary vasculitis
    Additional description: Pulmonary vasculitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
    Additional description: Vasculitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 85 (4.71%)
    3 / 18 (16.67%)
    9 / 85 (10.59%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    General disorders and administration site conditions
    Chest pain
    Additional description: Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perforated ulcer
    Additional description: Perforated ulcer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
    Additional description: Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stenosis
    Additional description: Stenosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Conversion disorder
    Additional description: Conversion disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accident
    Additional description: Accident
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
    Additional description: Fall
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
    Additional description: Intra-abdominal haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
    Additional description: Post procedural complication
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
    Additional description: Subdural haematoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular access complication
    Additional description: Vascular access complication
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
    Additional description: Wound dehiscence
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Medical observation
    Additional description: Medical observation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
    Additional description: Transaminases increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
    Additional description: Acute coronary syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
    Additional description: Acute myocardial infarction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
    Additional description: Atrial fibrillation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
    Additional description: Atrioventricular block complete
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
    Additional description: Cardiac arrest
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
    Additional description: Cardiac failure congestive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
    Additional description: Cardiomyopathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
    Additional description: Coronary artery disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
    Additional description: Myocardial infarction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
    Additional description: Iron deficiency anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
    Additional description: Neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
    Additional description: Bronchospasm
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
    Additional description: Chronic obstructive pulmonary disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
    Additional description: Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal stenosis
    Additional description: Laryngeal stenosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumomediastinum
    Additional description: Pneumomediastinum
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
    Additional description: Pneumonitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
    Additional description: Pneumothorax
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stridor
    Additional description: Stridor
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
    Additional description: Cerebrovascular accident
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Haemorrhagic stroke
    Additional description: Haemorrhagic stroke
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
    Additional description: Sleep apnoea syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
    Additional description: Subdural haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Periorbital oedema
    Additional description: Periorbital oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 85 (3.53%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
    Additional description: Colitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
    Additional description: Duodenal ulcer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
    Additional description: Enterovesical fistula
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
    Additional description: Gastrointestinal haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia strangulated
    Additional description: Inguinal hernia strangulated
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
    Additional description: Intestinal perforation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    2 / 18 (11.11%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Oesophageal spasm
    Additional description: Oesophageal spasm
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
    Additional description: Oesophagitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
    Additional description: Pancreatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
    Additional description: Small intestinal obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Acute kidney injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    4 / 85 (4.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
    Additional description: Enterovesical fistula
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
    Additional description: Nephrolithiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
    Additional description: Proteinuria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
    Additional description: Renal impairment
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
    Additional description: Cholecystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
    Additional description: Cholecystitis acute
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
    Additional description: Cholelithiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
    Additional description: Intervertebral disc protrusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis
    Additional description: Myasthenia gravis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis crisis
    Additional description: Myasthenia gravis crisis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
    Additional description: Osteoarthritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pubis fracture
    Additional description: Pubis fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    Additional description: Dehydration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
    Additional description: Hyperglycaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
    Additional description: Hyperkalaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
    Additional description: Metabolic acidosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
    Additional description: Abdominal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
    Additional description: Appendicitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
    Additional description: Bronchitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
    Additional description: Cellulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
    Additional description: Cholecystitis infective
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Corona virus infection
    Additional description: Corona virus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Corynebacterium infection
    Additional description: Corynebacterium infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dacryocystitis
    Additional description: Dacryocystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
    Additional description: Diverticulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
    Additional description: Escherichia urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 18 (5.56%)
    3 / 85 (3.53%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Escherichia coli
    Additional description: Gastroenteritis Escherichia coli
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
    Additional description: Gastroenteritis viral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
    Additional description: Herpes zoster
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster meningoencephalitis
    Additional description: Herpes zoster meningoencephalitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
    Additional description: Infective exacerbation of chronic obstructive airways disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
    Additional description: Influenza
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    4 / 85 (4.71%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
    Additional description: Lower respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    4 / 85 (4.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metapneumovirus infection
    Additional description: Metapneumovirus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral herpes
    Additional description: Oral herpes
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital abscess
    Additional description: Periorbital abscess
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
    Additional description: Peritonitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 85 (7.06%)
    3 / 18 (16.67%)
    4 / 85 (4.71%)
         occurrences causally related to treatment / all
    8 / 8
    6 / 7
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
    Additional description: Pneumonia cytomegaloviral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
    Additional description: Pneumonia haemophilus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
    Additional description: Pneumonia klebsiella
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
    Additional description: Pneumonia pneumococcal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
    Additional description: Pneumonia pseudomonal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
    Additional description: Pneumonia staphylococcal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
    Additional description: Pneumonia streptococcal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
    Additional description: Pneumonia viral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
    Additional description: Postoperative wound infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
    Additional description: Progressive multifocal leukoencephalopathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonas infection
    Additional description: Pseudomonas infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
    Additional description: Respiratory syncytial virus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
    Additional description: Respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 85 (3.53%)
    4 / 18 (22.22%)
    7 / 85 (8.24%)
         occurrences causally related to treatment / all
    4 / 4
    7 / 9
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    Sepsis
    Additional description: Sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Serratia infection
    Additional description: Serratia infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
    Additional description: Sinusitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stenotrophomonas infection
    Additional description: Stenotrophomonas infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic viral infection
    Additional description: Systemic viral infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
    Additional description: Upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
    Additional description: Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
    Additional description: Viral infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
    Additional description: Wound infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Rituximab Induction Azathioprine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 85 (70.59%)
    7 / 18 (38.89%)
    66 / 85 (77.65%)
    Investigations
    Streptococcus test positive
    Additional description: Streptococcus test positive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
    Additional description: Basal cell carcinoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    1
    0
    2
    Gastrointestinal carcinoma
    Additional description: Gastrointestinal carcinoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences all number
    0
    1
    0
    Malignant melanoma
    Additional description: Malignant melanoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Oesophageal carcinoma
    Additional description: Oesophageal carcinoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Prostate cancer
    Additional description: Prostate cancer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Squamous cell carcinoma
    Additional description: Squamous cell carcinoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    3 / 85 (3.53%)
         occurrences all number
    0
    2
    5
    Eye disorders
    Blepharitis
    Additional description: Blepharitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Malaise
    Additional description: Malaise
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Cheilitis
    Additional description: Cheilitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Cholecystitis
    Additional description: Cholecystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Eczema
    Additional description: Eczema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Rosacea
    Additional description: Rosacea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Bacterial dacryocystitis
    Additional description: Bacterial dacryocystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Bacterial infection
    Additional description: Bacterial infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    2
    0
    0
    Beta haemolytic streptococcal infection
    Additional description: Beta haemolytic streptococcal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Body tinea
    Additional description: Body tinea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchitis
    Additional description: Bronchitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    2
    0
    0
    Bronchitis haemophilus
    Additional description: Bronchitis haemophilus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    2
    0
    1
    Candida infection
    Additional description: Candida infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 18 (5.56%)
    2 / 85 (2.35%)
         occurrences all number
    1
    1
    2
    Cellulitis
    Additional description: Cellulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 85 (4.71%)
    0 / 18 (0.00%)
    5 / 85 (5.88%)
         occurrences all number
    4
    0
    7
    Cellulitis orbital
    Additional description: Cellulitis orbital
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Citrobacter infection
    Additional description: Citrobacter infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    1
    0
    1
    Clostridium difficile infection
    Additional description: Clostridium difficile infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctivitis
    Additional description: Conjunctivitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 85 (3.53%)
    0 / 18 (0.00%)
    3 / 85 (3.53%)
         occurrences all number
    4
    0
    3
    Cystitis
    Additional description: Cystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    2
    0
    0
    Cystitis escherichia
    Additional description: Cystitis escherichia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    1
    0
    4
    Cystitis klebsiella
    Additional description: Cystitis klebsiella
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Cytomegalovirus colitis
    Additional description: Cytomegalovirus colitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences all number
    0
    1
    0
    Cytomegalovirus infection
    Additional description: Cytomegalovirus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences all number
    0
    1
    0
    Diverticulitis
    Additional description: Diverticulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Ear infection
    Additional description: Ear infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 85 (5.88%)
    0 / 18 (0.00%)
    4 / 85 (4.71%)
         occurrences all number
    7
    0
    6
    Enterococcal infection
    Additional description: Enterococcal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Escherichia urinary tract infection
    Additional description: Escherichia urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 85 (3.53%)
    0 / 18 (0.00%)
    4 / 85 (4.71%)
         occurrences all number
    7
    0
    6
    Eye infection
    Additional description: Eye infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    3 / 85 (3.53%)
         occurrences all number
    0
    0
    5
    Folliculitis
    Additional description: Folliculitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    2
    Gastrointestinal infection
    Additional description: Gastrointestinal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Haemophilus infection
    Additional description: Haemophilus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    4 / 85 (4.71%)
         occurrences all number
    3
    0
    4
    Herpes simplex
    Additional description: Herpes simplex
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    0
    0
    2
    Herpes zoster
    Additional description: Herpes zoster
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    1
    0
    1
    Infected skin ulcer
    Additional description: Infected skin ulcer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Infection
    Additional description: Infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    1
    0
    2
    Klebsiella infection
    Additional description: Klebsiella infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Lower respiratory tract infection
    Additional description: Lower respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    7 / 85 (8.24%)
         occurrences all number
    3
    0
    12
    Lung infection
    Additional description: Lung infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Mastoiditis
    Additional description: Mastoiditis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Oesophageal candidiasis
    Additional description: Oesophageal candidiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Oral candidiasis
    Additional description: Oral candidiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 85 (3.53%)
    1 / 18 (5.56%)
    5 / 85 (5.88%)
         occurrences all number
    3
    1
    7
    Oral herpes
    Additional description: Oral herpes
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    0
    0
    2
    Otitis media
    Additional description: Otitis media
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    0
    0
    2
    Parasitic gastroenteritis
    Additional description: Parasitic gastroenteritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Paronychia
    Additional description: Paronychia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    2
    0
    0
    Pharyngitis
    Additional description: Pharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    2
    0
    2
    Pneumonia
    Additional description: Pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 85 (3.53%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    3
    0
    1
    Pneumonia haemophilus
    Additional description: Pneumonia haemophilus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    4
    0
    2
    Pneumonia klebsiella
    Additional description: Pneumonia klebsiella
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Pneumonia pneumococcal
    Additional description: Pneumonia pneumococcal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    2
    0
    0
    Pneumonia pseudomonal
    Additional description: Pneumonia pseudomonal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonia staphylococcal
    Additional description: Pneumonia staphylococcal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Prostate infection
    Additional description: Prostate infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Proteus infection
    Additional description: Proteus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    2
    0
    0
    Pseudomonas bronchitis
    Additional description: Pseudomonas bronchitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 85 (3.53%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    3
    0
    3
    Pseudomonas infection
    Additional description: Pseudomonas infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Respiratory tract infection
    Additional description: Respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    25 / 85 (29.41%)
    1 / 18 (5.56%)
    35 / 85 (41.18%)
         occurrences all number
    58
    6
    73
    Respiratory tract infection viral
    Additional description: Respiratory tract infection viral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Root canal infection
    Additional description: Root canal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Serratia infection
    Additional description: Serratia infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 18 (5.56%)
    0 / 85 (0.00%)
         occurrences all number
    0
    1
    0
    Sinusitis
    Additional description: Sinusitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 85 (17.65%)
    3 / 18 (16.67%)
    16 / 85 (18.82%)
         occurrences all number
    35
    4
    24
    Skin infection
    Additional description: Skin infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 85 (5.88%)
    0 / 18 (0.00%)
    5 / 85 (5.88%)
         occurrences all number
    5
    0
    5
    Staphylococcal impetigo
    Additional description: Staphylococcal impetigo
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Staphylococcal infection
    Additional description: Staphylococcal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 85 (4.71%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    4
    0
    3
    Systemic infection
    Additional description: Systemic infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Tinea infection
    Additional description: Tinea infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Tinea pedis
    Additional description: Tinea pedis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Tonsillitis
    Additional description: Tonsillitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Tonsillitis bacterial
    Additional description: Tonsillitis bacterial
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Tooth abscess
    Additional description: Tooth abscess
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    3 / 85 (3.53%)
         occurrences all number
    1
    0
    4
    Tooth infection
    Additional description: Tooth infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 85 (3.53%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    3
    0
    0
    Upper respiratory tract infection
    Additional description: Upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    19 / 85 (22.35%)
    2 / 18 (11.11%)
    22 / 85 (25.88%)
         occurrences all number
    23
    2
    33
    Urinary tract infection
    Additional description: Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 85 (11.76%)
    1 / 18 (5.56%)
    8 / 85 (9.41%)
         occurrences all number
    13
    1
    13
    Urinary tract infection enterococcal
    Additional description: Urinary tract infection enterococcal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    2
    0
    1
    Vaginal infection
    Additional description: Vaginal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Varicella zoster virus infection
    Additional description: Varicella zoster virus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 18 (0.00%)
    1 / 85 (1.18%)
         occurrences all number
    0
    0
    1
    Viral infection
    Additional description: Viral infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    1
    0
    0
    Vulvovaginal candidiasis
    Additional description: Vulvovaginal candidiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 18 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    2
    0
    3
    Vulvovaginal mycotic infection
    Additional description: Vulvovaginal mycotic infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 18 (0.00%)
    0 / 85 (0.00%)
         occurrences all number
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2013
    New PIS/consent v2.0
    12 Sep 2013
    Protocol v 2.0; Consent - Minor assent form v1.1; PROMIS Questionnaire v2.0; PIS/consent v3.0 1) Addition of patient related outcome questionnaire (PROMIS). 2) Change to dosing advice for azathioprine in older patients. There is limited, objective evidence to support dose reduction of azathioprine with age. This is an historic practice, and would risk under-dosing our comparator group in the trial, possibly masking true treatment effects. The safety parameters and monitoring of azathioprine remain unchanged, and are robust to detect any problems early. 3) Simplification of oral prednisolone dosing by conversion from mg/kg/day to mg/day with two weight divisions. The protocol was written to provide 2 prednisolone regimens (0.5mg/kg or 1.0mg/kg) for investigators to ‘tailor’ according to the severity of disease manifestations of the patient. The maximum daily dose was set at 60mg in week 0. However, due to the enrolment of two patients into the trial with larger than average Body Mass Index, it became necessary to redesign the regimens according to body weight to take account of this. This is also an important safety measure since adverse reactions to high prednisolone doses are well documented. Clarity has been added to the instruction paragraph for treatment of patient relapse during the trial since there was disagreement in the protocol between earlier instructions. This corrects and clarifies the wording. 4) Change of inclusion/exclusion criteria 5) Reference Safety Information change 6) Rewording of the safety section of the protocol 7) Alignment of follow up assessments for non-randomised patients 8) Clarification of Hepatitis B screening to include new safety information
    08 May 2014
    Addition of 4 new UK sites (applies to Dudley only the other sites did not set up)
    17 Sep 2015
    Consent - Minor assent form v2.0; PIS parent/guardian v4.0; PIS/consent v4.0; Protocol v3.0; 1) Clarification of the number of patients that will be randomised The protocol now reads that at least 160 patients will be randomised, to account for the fact that some patients may have been recruited, but not yet reached the 4 month randomisation point when the target of 160 patients is reached, thus allowing them to continue into the maintenance phase of the trial. 2) Clarification of practicalities of trial A section has been added to the synopsis to make clear the three phases of the trial; further details on the minimisation criteria for randomisation have been added; clarification of the process of screening for pregnancy at the baseline visit has been added as well as additional information for investigators in the Republic of Ireland regarding contraception advice; it is now made clear that rituximab, azathioprine, methotrexate and mycophenolate mofetil are all IMPs for the purpose of this study; further detail regarding actions if IgG levels fall to below 3g/l have been added. Reducing dose of MTX and MMF by 50% at month 24 and then complete withdrawal at month 27, to align with azathioprine 3) Re-wording of the primary objective It now reads “To assess the efficacy of rituximab compared to azathioprine in the prevention of disease flare in AAV patients with relapsing disease”, rather than “To demonstrate the superiority of rituximab against azathioprine in the prevention of disease flare in AAV patients with relapsing disease” 4) Safety reporting Kim Mynard has replaced Michelle Lewin as trial coordinator, and therefore the reporting contact for SAEs has been updated to reflect this. Section 13 has been re-worded and re-formatted to clarify the reference safety information for the trial and the definition of expected adverse reactions. In addition, several adverse events of interest will now be collected as part of the study.
    05 Nov 2015
    Addition of 3 new UK sites (applies to Leicester and East Kent only) Stevenage did not set up
    04 Feb 2016
    Amendment to CTA
    14 Nov 2016
    Change in PI at Ipswich site
    27 Jun 2017
    Change in RSI; Protocol v4.0 1) Safety reporting Section 11 has been updated to include new reference safety information provided in the Azathioprine and Mycophenolate Mofetil SmPCs. Section 13 has been updated to include new reference safety information provided in the Azathioprine and Mycophenolate Mofetil SmPCs relating to adverse effects and pregnancy. Section 13.1.6 has been updated to clarify the definition of RSI for comparators (UK patients only).
    26 Jul 2017
    New PIS/consent v5.0
    02 Aug 2017
    Change in PI at Ipswich site
    19 Feb 2018
    Change of secondary packaging for IMP PR1 (Rituximab) for this trial
    04 Sep 2018
    Update to PIS v6.0 and Protocol v5.0 and update to RSI 1) Safety reporting Sections 11 and 13 have been updated to include the monographs for azathioprine, methotrexate and mycophenolate mofetil as reference safety information for Canada. Sections 11 and 13 have been updated to remove text regarding monitoring assessments for azathioprine, methotrexate and mycophenolate mofetil. Section 11 has been updated to include new reference safety information provided in the Methotrexate SmPC. Several minor changes have also been made to the trial documentation.
    19 Aug 2019
    Change in PI at Leicester site

    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.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/32581088
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