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    Clinical Trial Results:
    Addition of Rituximab to Leflunomide in patients with active rheumatoid arthritis

    Summary
    EudraCT number
    		 2009-015950-39
    Trial protocol
    		 DE  
    Global end of trial date
    17 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Nov 2021
    First version publication date
    11 Nov 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    FFM07-Rtx-Lef
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01244958
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Goethe-University Frankfurt
    Sponsor organisation address
    Theodor-Stern-Kai 7, Frankfurt am Main, Germany, 6
    Public contact
    Prof. Dr. Harald Burkhardt, Department of Rheumatology University Hospital Goethe–University of Frankfurt, 0049 69 6301 7302, Harald.Burkhardt@kgu.de
    Scientific contact
    Prof. Dr. Harald Burkhardt, Department of Rheumatology University Hospital Goethe–University of Frankfurt, 0049 69 6301 7302, Harald.Burkhardt@kgu.de
    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
    15 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part I To determine the efficacy and safety at week 24 of rituximab treatment of 1000 mg i.v. versus placebo when used on top of leflunomide in patients with active rheumatoid arthritis that currently have an inadequate response to leflunomide • Proportion of patients with an ACR 50 response at week 24. Part II To determine the efficacy at week 52 of rituximab treatment of two times 1000 mg vs. two times 500 mg rituximab in weeks 24 and 26 respectivley in patients who completed Part I and were treated in Part I with 2x1000mg rituximab. • Mean of DAS28 at week 52
    Protection of trial subjects
    atients who have had an initial response to IMP < 0.6 (DAS28) or less than 20% improvement in both TJC and SJC will receive “rescue treatment” (“standard of care”) between week 16 and week 24. “Rescue” treatment with any “standard of care treatment”, is at the discretion of the treating investigator.
    Background therapy
    		 All patients will receive concomitant leflunomide 10-20 mg / day at a stable dose as prescribed by the treating physician and in accordance with the local label. In case of toxicity due to leflunomide a reduction to not less than 10 mg is allowed. All patients should continue to receive any background glucocorticoids (≤ 10 mg / day prednisone or equivalent) or oral nonsteroidal anti-inflammatory drugs (NSAIDs) at a stable dose.
    Evidence for comparator
    		 comparison was to Placebo
    Actual start date of recruitment
    18 Aug 2010
    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
    Germany: 149
    Worldwide total number of subjects
    149
    EEA total number of subjects
    149
    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)
    115
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment period from 18.08.2010 until 06.01.2014 in 47 sites in Germany

    Pre-assignment
    Screening details
    		 189 patients were screened. Thereof 41 were screening failure due to withdrawal of inormed consent (n=10), 28 that fail to meet inclusion/exclusion criteria in the period until randomization, and 3 due to other reasons. Screening period could be up to 34 before baseline visit including randomization. 149 subjects were randomized only 140 treated

    Pre-assignment period milestones
    Number of subjects started
    		 149
    Number of subjects completed
    		 140

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 2
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Reason: Number of subjects
    		 other: 4
    Period 1
    Period 1 title
    part I
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Rituximab and PLC were blinded and not distinguishable in their vial. Measurement of B-lymphocytes concentration were not provided to investigators and project management to hinder unblinding due to rituximabs ability to deplete the B-lymphocytes

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 Verum arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    MabThera®
    Investigational medicinal product code
    EU/1/98/067/002
    Other name
    Rituximab
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Infusion on day 1 and 14 - Part I two times 1000mg - Part I

    Arm title
    		 Control
    Arm description
    		 Placebo to Rituximab
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo to rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    twice two vials of Placebo given Day 1 and Day 15

    Number of subjects in period 1 [1]
    		Rituximab Control
    Started
    93
    47
    Completed
    75
    35
    Not completed
    18
    12
         other
    18
    12
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 180 subjects were screened, 149 subjects were enrolled but only 140 were randomized and received treatment. That are the subjects treated and analysed in part I of the study.
    Period 2
    Period 2 title
    part II
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject
    Blinding implementation details
    Retreatment was consists of two vials - for the lower dosage placebo was added as second vial resulting in a 50% reduced dosage of RTX

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Retreatment 1000 _ P1
    Arm description
    		 Retreatment with twice 1000 mg Rituximab and Placebo in Part 1 of the study
    Arm type
    		 Experimental

    Investigational medicinal product name
    MabThera®
    Investigational medicinal product code
    EU/1/98/067/002
    Other name
    Rituximab
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    two times 1000mg - Part I separted by 14 days

    Arm title
    		 Retreatment 500 _P2
    Arm description
    		 Retreatment starting at week 24 with twice 500 mg Rituximab 14 days apart and Placebo in Part 1 of the study
    Arm type
    		 Experimental

    Investigational medicinal product name
    MabThera®
    Investigational medicinal product code
    EU/1/98/067/002
    Other name
    Rituximab
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    two times 500 mg - Part II

    Arm title
    		 Retreatment 1000 _V1
    Arm description
    		 Retreatment with twice 1000 mg Rituximab and Verum (RTX) in Part 1 of the study
    Arm type
    		 Retreatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Retreatment 500 _V2
    Arm description
    		 Retreatment starting at week 24 with twice 500 mg Rituximab 14 days apart and verum (RTX) in Part 1 of the study
    Arm type
    		 Retreatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [2]
    		Retreatment 1000 _ P1 Retreatment 500 _P2 Retreatment 1000 _V1 Retreatment 500 _V2
    Started
    10
    12
    30
    30
    Completed
    8
    10
    28
    30
    Not completed
    2
    2
    2
    0
         other
    2
    2
    2
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Some of the patients did not continue the part II of the study - they switched to rescue treatment or did not want to continue the study therefor there is a discrepancy between end of part I and beginning of part II of the study

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    part I
    Reporting group description
    		 -

    Reporting group values
    		 part I Total
    Number of subjects
    		 140 140
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 57 (22 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 104 104
        Male
    		 36 36
    ethnic group
    Ethnical group at Screening visit
    Units: Subjects
        caucasian
    		 138 138
        other
    		 2 2

    End points

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    End points reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Verum arm

    Reporting group title
    Control
    Reporting group description
    		 Placebo to Rituximab
    Reporting group title
    Retreatment 1000 _ P1
    Reporting group description
    		 Retreatment with twice 1000 mg Rituximab and Placebo in Part 1 of the study

    Reporting group title
    Retreatment 500 _P2
    Reporting group description
    		 Retreatment starting at week 24 with twice 500 mg Rituximab 14 days apart and Placebo in Part 1 of the study

    Reporting group title
    Retreatment 1000 _V1
    Reporting group description
    		 Retreatment with twice 1000 mg Rituximab and Verum (RTX) in Part 1 of the study

    Reporting group title
    Retreatment 500 _V2
    Reporting group description
    		 Retreatment starting at week 24 with twice 500 mg Rituximab 14 days apart and verum (RTX) in Part 1 of the study

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    all subject results are described for the mITT - Modified Intent-to-Treat Population (mITT) The modified Intent-to-treat population (mITT) was defined to include all patients who received at least one dose of study medication and where the ACR Criteria (Part I) or DAS28 (Part II) was measured at least once under study medication. This population was the basis for confirmatory testing.

    Primary: Proportion of patients with an ACR 50 response at week 24

    		 Close Top of page
    End point title
    		 Proportion of patients with an ACR 50 response at week 24
    End point description
    To determine the efficacy and safety at week 24 of rituximab treatment of 2x1000 mg i.v. vs. placebo when used on top of leflunomide in patients with active rheumatoid arthritis that currently have an inadequate response to leflunomide
    End point type
    Primary
    End point timeframe
    Baseline until week 24
    End point values
    		 Rituximab Control mITT
    Number of subjects analysed
    93
    47
    Units: number
    22
    7
    140
    Statistical analysis title
    		 hypothesis testing
    Statistical analysis description
    The primary objective of Part I is to prove significant superiority in primary efficacy variable ACR50 response of arm V (LEF + 2×1000 mg Rituximab) as compared to arm P (LEF +2×PLC). i.e. the null hypothesis. H0: Prob (responder at week 24 under RTX+LEF) ≤ Prob (responder at week 24 under PLC+LEF) is to be rejected in favour of H1: Prob (responder at week 24 under RTX+LEF) > Prob (responder at week 24 under PLC+LEF) using a one-sided Cochran-Mantel Haenszel test at the 0.025 level. Types of An
    Comparison groups
    Rituximab v Control
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Primary: Mean of DAS28 at week 52

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    End point title
    		 Mean of DAS28 at week 52 [1]
    End point description
    To determine the efficacy at week 52 of rituximab treatment of 1000 mg at week 24 and 1000 mg at week 26 i.v. vs. 500 mg rituximab at week 24 and 500 mg rituximab at week 26 in patients who completed Part I and were treated in Part I with 2x1000 mg rituximab.
    End point type
    Primary
    End point timeframe
    week 52
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: only descriptive analysis done
    End point values
    		 Retreatment 1000 _ P1 Retreatment 500 _P2 Retreatment 1000 _V1 Retreatment 500 _V2
    Number of subjects analysed
    10
    12
    30
    30
    Units: number
        median (inter-quartile range (Q1-Q3))
    2.64 (2.09 to 4.24)
    2.47 (2.26 to 3.45)
    3.03 (2.32 to 3.90)
    2.92 (2.16 to 3.82)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to week 52
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Verum Part 1
    Reporting group description
    		 subjects treated in Part I with 1000 mg Rituximab (RTX)

    Reporting group title
    Placebo _ P
    Reporting group description
    		 Subjects treated with Placebo to RTX in part I

    Reporting group title
    Retreatment 1000 mg _V1
    Reporting group description
    		 subjects retreated in part II with 1000mg Rituximab and verum in part I

    Reporting group title
    Retreatment 1000 mg _P1
    Reporting group description
    		 subjects retreated in part II with 1000mg Rituximab and placebo in part I

    Reporting group title
    Retreatment 500 mg_V2
    Reporting group description
    		 subjects retreated in part II with 500 mg Rituximab and verum in part I

    Reporting group title
    Retreatment 500 mg_P2
    Reporting group description
    		 subjects retreated in part II with 1000mg Rituximab and placebo in part I

    Serious adverse events
    		 Verum Part 1 Placebo _ P Retreatment 1000 mg _V1 Retreatment 1000 mg _P1 Retreatment 500 mg_V2 Retreatment 500 mg_P2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 93 (20.43%)
    1 / 47 (2.13%)
    1 / 30 (3.33%)
    1 / 10 (10.00%)
    3 / 30 (10.00%)
    3 / 12 (25.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigation abnormal
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric neoplasm
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Tendon rupture
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin flap necrosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bunion operation
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint arthroplasty
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angioplasty
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc operation
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal operation
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon calcification
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Arthropathy
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Verum Part 1 Placebo _ P Retreatment 1000 mg _V1 Retreatment 1000 mg _P1 Retreatment 500 mg_V2 Retreatment 500 mg_P2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 93 (74.19%)
    35 / 47 (74.47%)
    22 / 30 (73.33%)
    5 / 10 (50.00%)
    21 / 30 (70.00%)
    10 / 12 (83.33%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastric neoplasm
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Haemangioma of liver
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 93 (11.83%)
    5 / 47 (10.64%)
    2 / 30 (6.67%)
    2 / 10 (20.00%)
    1 / 30 (3.33%)
    1 / 12 (8.33%)
         occurrences all number
    14
    9
    3
    2
    1
    1
    Hypotension
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 47 (2.13%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    1
    0
    1
    1
    Haematoma
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hypertensive crisis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    1 / 10 (10.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    Lymphoedema
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    2
    0
    Peripheral venous disease
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Flushing
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Arterial occlusive disease
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Surgical and medical procedures
    Bunion operation
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dental care
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Intervertebral disc operation
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Nasal operation
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Joint arthroplasty
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Synovectomy
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Angioplasty
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 93 (2.15%)
    2 / 47 (4.26%)
    2 / 30 (6.67%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    2
    0
    1
    1
    Chills
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Impaired healing
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 93 (0.00%)
    3 / 47 (6.38%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    Device dislocation
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Death
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Malaise
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Device breakage
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Face oedema
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Oedema
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    menorrhagia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Amenorrhoea
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ovarian cyst
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 47 (2.13%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    1 / 10 (10.00%)
    1 / 30 (3.33%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    1
    1
    1
    1
    Throat irritation
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Rales
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Respiratory disorder
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Sputum discoloured
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Emphysema
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 93 (3.23%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    Enzyme level increased
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 93 (2.15%)
    2 / 47 (4.26%)
    2 / 30 (6.67%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    2
    0
    1
    0
    Blood creatine increased
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    2 / 30 (6.67%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    2
    0
    Bacterial test
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    White blood cell count increased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Investigation abnormal
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Weight increased
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Laboratory test abnormal
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Urine analysis abnormal
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Foot fracture
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Tendon rupture
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin flap necrosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Traumatic haematoma
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    Joint dislocation
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Contusion
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Muscle strain
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ulna fracture
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Excoriation
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Muscle rupture
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Anomalous arrangement of pancreaticobiliary duct
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Tachycardia paroxysmal
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Angina pectoris
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Bradycardia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    3 / 93 (3.23%)
    1 / 47 (2.13%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    1
    0
    0
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 47 (4.26%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Migraine
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    0
    0
    3
    1
    Headache
         subjects affected / exposed
    3 / 93 (3.23%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    1 / 12 (8.33%)
         occurrences all number
    4
    1
    0
    0
    1
    1
    Dysgeusia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 93 (1.08%)
    2 / 47 (4.26%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    3
    0
    0
    1
    0
    Cubital tunnel syndrome
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Thrombocytosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Anaemia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Lymphopenia
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Eosinopenia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    2 / 30 (6.67%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    Anaemia folate deficiency
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 47 (2.13%)
    1 / 30 (3.33%)
    1 / 10 (10.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    2
    1
    1
    0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Maculopathy
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Presbyopia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Gastric disorder
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    8 / 93 (8.60%)
    7 / 47 (14.89%)
    2 / 30 (6.67%)
    2 / 10 (20.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    9
    8
    2
    2
    0
    0
    Gastric ulcer
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Aphthous ulcer
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pancreatitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Crohn's disease
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Colitis ulcerative
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastritis erosive
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Oesophagitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Hepatitis cholestatic
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Liver disorder
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cholestasis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cholelithiasis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hepatic steatosis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Papule
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    2
    0
    Dermatitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Nail discolouration
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    3 / 93 (3.23%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
    0 / 12 (0.00%)
         occurrences all number
    4
    0
    1
    0
    2
    0
    Eczema
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Vitiligo
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Erythema
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 93 (1.08%)
    2 / 47 (4.26%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Acne
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    Skin plaque
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dry skin
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eczema asteatotic
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin ulcer
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dandruff
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Glycosuria
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Renal cyst
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Incontinence
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Leukocyturia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Myxoedema
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 47 (2.13%)
    1 / 30 (3.33%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    1
    1
    0
    0
    Arthralgia
         subjects affected / exposed
    3 / 93 (3.23%)
    2 / 47 (4.26%)
    0 / 30 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    2
    0
    1
    0
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    1 / 10 (10.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    1
    2
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    0
    0
    0
    1
    Rheumatoid arthritis
         subjects affected / exposed
    9 / 93 (9.68%)
    2 / 47 (4.26%)
    0 / 30 (0.00%)
    1 / 10 (10.00%)
    3 / 30 (10.00%)
    1 / 12 (8.33%)
         occurrences all number
    9
    2
    0
    1
    4
    1
    Bursitis
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Osteopenia
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Spinal pain
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Sacroiliitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Synovial cyst
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Osteochondrosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Enthesopathy
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Tendon calcification
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Tenosynovitis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Arthropathy
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 93 (1.08%)
    2 / 47 (4.26%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    3
    0
    0
    1
    0
    Osteonecrosis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Joint effusion
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Arthritis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Tendonitis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 93 (11.83%)
    6 / 47 (12.77%)
    7 / 30 (23.33%)
    2 / 10 (20.00%)
    13 / 30 (43.33%)
    2 / 12 (16.67%)
         occurrences all number
    12
    6
    9
    2
    14
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Cystitis
         subjects affected / exposed
    3 / 93 (3.23%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    8 / 93 (8.60%)
    2 / 47 (4.26%)
    2 / 30 (6.67%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    9
    2
    2
    0
    0
    0
    Paronychia1
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 93 (3.23%)
    2 / 47 (4.26%)
    1 / 30 (3.33%)
    1 / 10 (10.00%)
    1 / 30 (3.33%)
    1 / 12 (8.33%)
         occurrences all number
    3
    2
    2
    1
    1
    2
    Oral herpes
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    Abdominal wall abscess
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    4 / 93 (4.30%)
    2 / 47 (4.26%)
    5 / 30 (16.67%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    5
    2
    6
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Pulpitis dental
         subjects affected / exposed
    3 / 93 (3.23%)
    1 / 47 (2.13%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    1
    0
    2
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    2 / 93 (2.15%)
    2 / 47 (4.26%)
    2 / 30 (6.67%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    5
    2
    2
    0
    1
    0
    Febrile infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Erysipelas
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    Localised infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Breast abscess
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Otitis media
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Acute sinusitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Urosepsis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    lung infection
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 47 (4.26%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Erythema migrans
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Tonsillitis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Arthritis infective
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Onychomycosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Lymphangitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    1 / 10 (10.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Glucose tolerance impaired
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vitamin B complex deficiency
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gout
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 47 (2.13%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 47 (0.00%)
    0 / 30 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2011
    Patients with anti-TNF-inhibitor pre-treatment to be allowed
    07 May 2012
    Protocol was to be amended due to update in safety information to mabthera
    16 Sep 2013
    Due to insufficient recruitment sample size was adjusted
    26 Jan 2015
    Changes in data management procedures to be updated in protocol

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33738492
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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