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    Clinical Trial Results:
    A 2 year prospective multicentre randomised controlled trial comparing effectiveness in daily practice of different treatment strategies for early RA

    Summary
    EudraCT number
    		 2008-007225-39
    Trial protocol
    		 BE  
    Global end of trial date
    30 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2018
    First version publication date
    27 Dec 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CareRA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01172639
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospitals Leuven
    Sponsor organisation address
    herestraat 49, Leuven, Belgium, 3000
    Public contact
    Patrick Verschueren, University Hospitals Leuven, 32 1634 25 41, patrick.verschueren@uz.kuleuven.ac.be
    Scientific contact
    Patrick Verschueren, University Hospitals Leuven, 32 1634 25 41, patrick.verschueren@uz.kuleuven.ac.be
    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
    01 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To study in patients with severe RA, the efficacy and effectiveness of a classic COBRA scheme (with 15mg MTX) versus two modified COBRA schemes respectively “slim” (without SSZ and with half dose steroids) and “avant-garde” (leflunomide instead of SSZ and half dose steroids) in daily practice. To study in patients with less severe RA, the daily practice efficacy and effectiveness of a tight step up regimen (with 15mg MTX) versus a modified COBRA slim scheme (without SSZ and with half dose steroids).
    Protection of trial subjects
    pragmatic trial rooted in daily practice, patient were started on therapy based on the remission induction principle and were followed by the treat to target principle which means treatment adaptations were done whenever patients failed to comply with low disease activity as defined in the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Feb 2009
    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
    Belgium: 379
    Worldwide total number of subjects
    379
    EEA total number of subjects
    379
    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)
    318
    From 65 to 84 years
    61
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 400 participants were recruited between Januari 2009 and May 2013. There were patients included in 13 Flemish rheumatology centers (2 academic centers, 7 general hospitals and 4 private practices)

    Pre-assignment
    Screening details
    		 there were 400 patients screened of which 379 were randomised to a treatment arm, 21 patients were not randomised: 1 screen failure, 10 withdrawals by subject, 10 randomisation errors

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CoBRA Classic High Risk Group
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ledertrexate
    Investigational medicinal product code
    PA1327/009/001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total dose of maximum 20 mg weekly (range from 7.5 to 20 mg weekly)

    Investigational medicinal product name
    Salazopyrine
    Investigational medicinal product code
    PA187/51/3
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total dose of maximum 3gr (range from 1 to 3 gr daily) for a period of 40 weeks

    Investigational medicinal product name
    prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    weekly step down scheme starting with 60-40-25-20-15-10 mg daily for 6 weeks, followed by 7.5mg daily till week 28 of treatment then tapered down to stop at week 32

    Arm title
    		 CoBRA Slim High Risk Group
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ledertrexate
    Investigational medicinal product code
    PA1327/009/001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total dose of maximum 20 mg weekly (range from 7.5 to 20 mg weekly)

    Investigational medicinal product name
    prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    weekly step down scheme starting with 30-20-12.5-10-7.5 mg daily for 5 weeks, followed by 5mg daily till week 28 of treatment then tapered down to stop at week 32

    Arm title
    		 CoBRA Avant-Garde High Risk group
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ledertrexate
    Investigational medicinal product code
    PA1327/009/001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total dose of maximum 20 mg weekly (range from 7.5 to 20 mg weekly)

    Investigational medicinal product name
    prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    weekly step down scheme starting with 30-20-12.5-10-7.5 mg daily for 5 weeks, followed by 5mg daily till week 28 of treatment then tapered down to stop at week 32

    Investigational medicinal product name
    Leflunomide
    Investigational medicinal product code
    EU/1/99/118/001-004
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    range 10-20 mg daily, oral intake

    Arm title
    		 CoBRA Slim Low Risk Group
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ledertrexate
    Investigational medicinal product code
    PA1327/009/001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total dose of maximum 20 mg weekly (range from 7.5 to 20 mg weekly)

    Investigational medicinal product name
    prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    weekly step down scheme starting with 30-20-12.5-10-7.5 mg daily for 5 weeks, followed by 5mg daily till week 28 of treatment then tapered down to stop at week 32

    Arm title
    		 Tight Step Up Low Risk Group
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ledertrexate
    Investigational medicinal product code
    PA1327/009/001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total dose of maximum 20 mg weekly (range from 7.5 to 20 mg weekly)

    Number of subjects in period 1
    		CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-Garde High Risk group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Started
    98
    98
    93
    43
    47
    Week 16
    94
    96
    91
    39
    47
    week 52
    89
    89
    88
    38
    45
    Completed
    85
    87
    77
    32
    41
    Not completed
    13
    11
    16
    11
    6
         Adverse event, serious fatal
    1
    1
    -
    -
    -
         Consent withdrawn by subject
    3
    3
    5
    5
    -
         Lost to follow-up
    9
    7
    11
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CoBRA Classic High Risk Group
    Reporting group description
    		 -

    Reporting group title
    CoBRA Slim High Risk Group
    Reporting group description
    		 -

    Reporting group title
    CoBRA Avant-Garde High Risk group
    Reporting group description
    		 -

    Reporting group title
    CoBRA Slim Low Risk Group
    Reporting group description
    		 -

    Reporting group title
    Tight Step Up Low Risk Group
    Reporting group description
    		 -

    Reporting group values
    		 CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-Garde High Risk group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group Total
    Number of subjects
    		 98 98 93 43 47 379
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 83 82 80 35 38 318
        From 65-84 years
    		 15 16 13 8 9 61
        85 years and over
    		 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.2 ( 11.9 ) 51.8 ( 13.1 ) 51.1 ( 13.1 ) 51.4 ( 14.4 ) 51.0 ( 14.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 64 63 64 33 38 262
        Male
    		 34 35 29 10 9 117
    RAce/Ethnicity
    Units: Subjects
        Caucasian
    		 95 96 90 43 47 371
        Hispanic
    		 0 0 0 0 0 0
        Asian
    		 2 1 0 0 0 3
        Black
    		 1 1 1 0 0 3
        North African
    		 0 0 2 0 0 2
    Smoking Status
    Units: Subjects
        Current
    		 30 30 23 10 4 97
        Past
    		 26 28 33 11 14 112
        Never
    		 42 40 37 22 29 170
    Symptom Duration
    Units: weeks
        arithmetic mean (standard deviation)
    		 33.8 ( 35.5 ) 33.2 ( 38.2 ) 44.3 ( 65.9 ) 34.4 ( 68.2 ) 33.1 ( 62.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    CoBRA Classic High Risk Group
    Reporting group description
    		 -

    Reporting group title
    CoBRA Slim High Risk Group
    Reporting group description
    		 -

    Reporting group title
    CoBRA Avant-Garde High Risk group
    Reporting group description
    		 -

    Reporting group title
    CoBRA Slim Low Risk Group
    Reporting group description
    		 -

    Reporting group title
    Tight Step Up Low Risk Group
    Reporting group description
    		 -

    Primary: remission according to DAS28-CRP at week 16

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    End point title
    		 remission according to DAS28-CRP at week 16
    End point description
    Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 16. DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRTSJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS). A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.
    End point type
    Primary
    End point timeframe
    week 16
    End point values
    		 CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-Garde High Risk group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Number of subjects analysed
    98
    98
    93
    43
    47
    Units: participants
    69
    72
    61
    25
    23
    Statistical analysis title
    		 proportion in remission at week 16
    Statistical analysis description
    number of patients in remission defined by a disease activity score based on the 28 joint count and C reactive protein (DAS28-CRP) < 2.6
    Comparison groups
    CoBRA Classic High Risk Group v CoBRA Slim High Risk Group v CoBRA Avant-Garde High Risk group v CoBRA Slim Low Risk Group v Tight Step Up Low Risk Group
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [1] - Population description, ITT (all randomised subjects included), missing data imputed with Expectation Maximization on complete w104 database.

    Primary: remission according to DAS28-CRP at week 52

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    End point title
    		 remission according to DAS28-CRP at week 52
    End point description
    Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 52. DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRTSJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS). A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.
    End point type
    Primary
    End point timeframe
    week 52
    End point values
    		 CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-Garde High Risk group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Number of subjects analysed
    98
    98
    93
    43
    47
    Units: participants
    63
    57
    57
    29
    29
    Statistical analysis title
    		 proportion of patients in remission at week 52
    Statistical analysis description
    number of patients in remission defined by a disease activity score based on the 28 joint count and C reactive protein (DAS28-CRP) < 2.6
    Comparison groups
    CoBRA Classic High Risk Group v CoBRA Slim High Risk Group v CoBRA Avant-Garde High Risk group v CoBRA Slim Low Risk Group v Tight Step Up Low Risk Group
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [2] - Population description, ITT (all randomised subjects included), missing data imputed with Expectation Maximization on complete w104 database.

    Primary: remission according to DAS28-CRP at week 104

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    End point title
    		 remission according to DAS28-CRP at week 104
    End point description
    Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 104. DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRTSJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS). A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.
    End point type
    Primary
    End point timeframe
    week 104
    End point values
    		 CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-Garde High Risk group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Number of subjects analysed
    98
    98
    93
    43
    47
    Units: participants
    64
    71
    69
    29
    34
    Statistical analysis title
    		 proportion of patients in remission at week 104
    Statistical analysis description
    number of patients in remission defined by a disease activity score based on the 28 joint count and C reactive protein (DAS28-CRP) < 2.6
    Comparison groups
    CoBRA Classic High Risk Group v CoBRA Slim High Risk Group v CoBRA Avant-Garde High Risk group v CoBRA Slim Low Risk Group v Tight Step Up Low Risk Group
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [3] - Population description, ITT (all randomised subjects included), missing data imputed with Expectation Maximization on complete w104 database.

    Secondary: remission according to SDAI at week 16

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    End point title
    		 remission according to SDAI at week 16
    End point description
    Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 16. SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS. A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.
    End point type
    Secondary
    End point timeframe
    week 16
    End point values
    		 CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-Garde High Risk group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Number of subjects analysed
    98
    98
    93
    43
    47
    Units: participants
    42
    33
    44
    12
    12
    Statistical analysis title
    		 proportion in remission at week 16 (SDAI)
    Statistical analysis description
    number of patients in remission defined by a simplified disease activity score (SDAI<=3.3)
    Comparison groups
    CoBRA Classic High Risk Group v CoBRA Slim High Risk Group v CoBRA Avant-Garde High Risk group v CoBRA Slim Low Risk Group v Tight Step Up Low Risk Group
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [4] - Population description, ITT (all randomised subjects included), missing data imputed with Expectation Maximization on complete w104 database.

    Secondary: remission according to SDAI at week 52

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    End point title
    		 remission according to SDAI at week 52
    End point description
    Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 52. SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS. A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.
    End point type
    Secondary
    End point timeframe
    week 52
    End point values
    		 CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-Garde High Risk group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Number of subjects analysed
    98
    98
    93
    43
    47
    Units: participants
    36
    27
    39
    20
    15
    Statistical analysis title
    		 proportion in remission at week 52 (SDAI)
    Statistical analysis description
    number of patients in remission defined by a simplified disease activity score (SDAI<=3.3)
    Comparison groups
    CoBRA Classic High Risk Group v CoBRA Slim High Risk Group v CoBRA Avant-Garde High Risk group v CoBRA Slim Low Risk Group v Tight Step Up Low Risk Group
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [5] - Population description, ITT (all randomised subjects included), missing data imputed with Expectation Maximization on complete w104 database.

    Secondary: remission according to SDAI at week 104

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    End point title
    		 remission according to SDAI at week 104
    End point description
    Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 104. SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS. A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.
    End point type
    Secondary
    End point timeframe
    week 104
    End point values
    		 CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-Garde High Risk group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Number of subjects analysed
    98
    98
    93
    43
    47
    Units: participants
    31
    28
    41
    20
    13
    Statistical analysis title
    		 proportion in remission at week 104(SDAI)
    Statistical analysis description
    number of patients in remission defined by a simplified disease activity score (SDAI<=3.3)
    Comparison groups
    CoBRA Classic High Risk Group v CoBRA Slim High Risk Group v CoBRA Avant-Garde High Risk group v CoBRA Slim Low Risk Group v Tight Step Up Low Risk Group
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [6] - Population description, ITT (all randomised subjects included), missing data imputed with Expectation Maximization on complete w104 database.

    Secondary: Clinically significant change in health assessment questionnaire (HAQ) score

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    End point title
    		 Clinically significant change in health assessment questionnaire (HAQ) score
    End point description
    Number of patients with a change of > 0.22 in the Health Assessment Questionnaire (HAQ) score over the period between baseline and week 104. A change of > 0.22 in this score is considered as clinical relevant for reumatoid arthritis patients.
    End point type
    Secondary
    End point timeframe
    Baseline to week 104
    End point values
    		 CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-Garde High Risk group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Number of subjects analysed
    98
    98
    93
    43
    47
    Units: participants
    71
    62
    64
    25
    26
    Statistical analysis title
    		 proportion of clinically significant change in HAQ
    Statistical analysis description
    Number of patients with a change of >w 0.22 in the HAQ.
    Comparison groups
    CoBRA Classic High Risk Group v CoBRA Slim High Risk Group v CoBRA Avant-Garde High Risk group v CoBRA Slim Low Risk Group v Tight Step Up Low Risk Group
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [7] - Population description, ITT (all randomised subjects included), missing data imputed with Expectation Maximization on complete w104 database.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected over a two year period per patient
    Adverse event reporting additional description
    All Adverse Events were registered by health care professionals questioning the patients at each visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    CoBRA Classic High Risk Group
    Reporting group description
    		 -

    Reporting group title
    CoBRA Slim High Risk Group
    Reporting group description
    		 -

    Reporting group title
    CoBRA Avant-Garde High Risk group
    Reporting group description
    		 -

    Reporting group title
    CoBRA Slim Low Risk Group
    Reporting group description
    		 -

    Reporting group title
    Tight Step Up Low Risk Group
    Reporting group description
    		 -

    Serious adverse events
    		 CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-Garde High Risk group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 98 (21.43%)
    22 / 98 (22.45%)
    16 / 93 (17.20%)
    9 / 43 (20.93%)
    7 / 47 (14.89%)
         number of deaths (all causes)
    1
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Baker's cyst excision
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Breast cancer
         subjects affected / exposed
    3 / 98 (3.06%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    1 / 93 (1.08%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    1 / 43 (2.33%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Lung carcinoma cell type unspecified recurrent
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Renal cell carcinoma
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    1 / 43 (2.33%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Lung operation
    Additional description: diagnostic resection of lung nodulus, benign nodule on pathology
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Parotid gland enlargement
    Additional description: neoplasm
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    1 / 93 (1.08%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nodule
    Additional description: nodule submandibular salivary gland
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abdominal operation
         subjects affected / exposed
    1 / 98 (1.02%)
    2 / 98 (2.04%)
    1 / 93 (1.08%)
    0 / 43 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amygdalotomy
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Hysterectomy
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    1 / 93 (1.08%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liposuction
    Additional description: upper limbs
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthopaedic procedure
         subjects affected / exposed
    2 / 98 (2.04%)
    1 / 98 (1.02%)
    4 / 93 (4.30%)
    0 / 43 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 6
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Anaphylactoid reaction
    Additional description: after wasp sting
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    1 / 93 (1.08%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    1 / 43 (2.33%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
    Additional description: peribronchitis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Mucositis management
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Injury, poisoning and procedural complications
    Post procedural complication
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    1 / 93 (1.08%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic delivery
         subjects affected / exposed
    1 / 98 (1.02%)
    2 / 98 (2.04%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    1 / 43 (2.33%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 98 (0.00%)
    3 / 98 (3.06%)
    1 / 93 (1.08%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
    Additional description: third degree
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    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
    Myocardial infarction
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Pain
    Additional description: diffuse pain
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    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
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    1 / 43 (2.33%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow disorder
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
    1 / 93 (1.08%)
    2 / 43 (4.65%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal polyp
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Oesophagitis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Cystitis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    1 / 43 (2.33%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Endocrine disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    2 / 93 (2.15%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Hernia diaphragmatic repair
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    1 / 93 (1.08%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    3 / 93 (3.23%)
    1 / 43 (2.33%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatic nerve neuropathy
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    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
    Hernia
    Additional description: Lumbago
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    1 / 93 (1.08%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
    Additional description: flare of reumatoid arthritis
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
    2 / 93 (2.15%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
    Additional description: septic bursitis olecrani
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 98 (0.00%)
    1 / 93 (1.08%)
    0 / 43 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-Garde High Risk group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    85 / 98 (86.73%)
    88 / 98 (89.80%)
    84 / 93 (90.32%)
    34 / 43 (79.07%)
    45 / 47 (95.74%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 98 (9.18%)
    8 / 98 (8.16%)
    13 / 93 (13.98%)
    4 / 43 (9.30%)
    1 / 47 (2.13%)
         occurrences all number
    9
    8
    13
    4
    1
    Syncope
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
    0 / 93 (0.00%)
    0 / 43 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    1
    0
    0
    0
    1
    Phlebitis
    Additional description: venous insufficiency
         subjects affected / exposed
    4 / 98 (4.08%)
    5 / 98 (5.10%)
    6 / 93 (6.45%)
    2 / 43 (4.65%)
    1 / 47 (2.13%)
         occurrences all number
    5
    5
    6
    2
    1
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    1 / 98 (1.02%)
    4 / 98 (4.08%)
    0 / 93 (0.00%)
    3 / 43 (6.98%)
    0 / 47 (0.00%)
         occurrences all number
    1
    4
    0
    3
    0
    General disorders and administration site conditions
    Agitation
         subjects affected / exposed
    6 / 98 (6.12%)
    2 / 98 (2.04%)
    10 / 93 (10.75%)
    3 / 43 (6.98%)
    0 / 47 (0.00%)
         occurrences all number
    7
    2
    10
    3
    0
    Dyspnoea
         subjects affected / exposed
    4 / 98 (4.08%)
    3 / 98 (3.06%)
    5 / 93 (5.38%)
    0 / 43 (0.00%)
    4 / 47 (8.51%)
         occurrences all number
    4
    4
    5
    0
    4
    Fatigue
         subjects affected / exposed
    7 / 98 (7.14%)
    4 / 98 (4.08%)
    4 / 93 (4.30%)
    2 / 43 (4.65%)
    5 / 47 (10.64%)
         occurrences all number
    7
    6
    5
    2
    5
    Flushing
         subjects affected / exposed
    6 / 98 (6.12%)
    4 / 98 (4.08%)
    2 / 93 (2.15%)
    2 / 43 (4.65%)
    0 / 47 (0.00%)
         occurrences all number
    6
    4
    2
    2
    0
    Malaise
    Additional description: general malaise
         subjects affected / exposed
    9 / 98 (9.18%)
    4 / 98 (4.08%)
    5 / 93 (5.38%)
    2 / 43 (4.65%)
    1 / 47 (2.13%)
         occurrences all number
    9
    4
    6
    2
    1
    Hair disorder
    Additional description: loss of hair
         subjects affected / exposed
    7 / 98 (7.14%)
    12 / 98 (12.24%)
    19 / 93 (20.43%)
    7 / 43 (16.28%)
    6 / 47 (12.77%)
         occurrences all number
    7
    13
    20
    7
    6
    Hyperhidrosis
         subjects affected / exposed
    7 / 98 (7.14%)
    3 / 98 (3.06%)
    6 / 93 (6.45%)
    3 / 43 (6.98%)
    1 / 47 (2.13%)
         occurrences all number
    7
    3
    7
    4
    1
    Insomnia
         subjects affected / exposed
    8 / 98 (8.16%)
    4 / 98 (4.08%)
    2 / 93 (2.15%)
    1 / 43 (2.33%)
    0 / 47 (0.00%)
         occurrences all number
    8
    4
    2
    1
    0
    Sjogren's syndrome
         subjects affected / exposed
    5 / 98 (5.10%)
    2 / 98 (2.04%)
    6 / 93 (6.45%)
    2 / 43 (4.65%)
    1 / 47 (2.13%)
         occurrences all number
    5
    2
    6
    2
    1
    Reproductive system and breast disorders
    Genital infection
         subjects affected / exposed
    2 / 98 (2.04%)
    2 / 98 (2.04%)
    8 / 93 (8.60%)
    1 / 43 (2.33%)
    0 / 47 (0.00%)
         occurrences all number
    2
    2
    9
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchitis
         subjects affected / exposed
    9 / 98 (9.18%)
    10 / 98 (10.20%)
    20 / 93 (21.51%)
    2 / 43 (4.65%)
    3 / 47 (6.38%)
         occurrences all number
    12
    10
    23
    2
    3
    Cough
         subjects affected / exposed
    9 / 98 (9.18%)
    13 / 98 (13.27%)
    7 / 93 (7.53%)
    1 / 43 (2.33%)
    1 / 47 (2.13%)
         occurrences all number
    9
    14
    7
    1
    1
    Dyspnoea
         subjects affected / exposed
    4 / 98 (4.08%)
    3 / 98 (3.06%)
    5 / 93 (5.38%)
    0 / 43 (0.00%)
    4 / 47 (8.51%)
         occurrences all number
    4
    4
    5
    0
    4
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 98 (28.57%)
    42 / 98 (42.86%)
    29 / 93 (31.18%)
    14 / 43 (32.56%)
    18 / 47 (38.30%)
         occurrences all number
    50
    72
    46
    29
    40
    Injury, poisoning and procedural complications
    Traumatic delivery
         subjects affected / exposed
    6 / 98 (6.12%)
    1 / 98 (1.02%)
    6 / 93 (6.45%)
    0 / 43 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    7
    1
    7
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    8 / 98 (8.16%)
    3 / 98 (3.06%)
    6 / 93 (6.45%)
    2 / 43 (4.65%)
    2 / 47 (4.26%)
         occurrences all number
    9
    3
    6
    2
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 98 (12.24%)
    6 / 98 (6.12%)
    9 / 93 (9.68%)
    2 / 43 (4.65%)
    3 / 47 (6.38%)
         occurrences all number
    14
    8
    12
    2
    3
    Skin discomfort
    Additional description: paresthesia
         subjects affected / exposed
    7 / 98 (7.14%)
    8 / 98 (8.16%)
    6 / 93 (6.45%)
    4 / 43 (9.30%)
    0 / 47 (0.00%)
         occurrences all number
    9
    8
    7
    5
    0
    Vertigo
         subjects affected / exposed
    11 / 98 (11.22%)
    7 / 98 (7.14%)
    6 / 93 (6.45%)
    4 / 43 (9.30%)
    3 / 47 (6.38%)
         occurrences all number
    11
    8
    7
    5
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 98 (8.16%)
    1 / 98 (1.02%)
    5 / 93 (5.38%)
    2 / 43 (4.65%)
    2 / 47 (4.26%)
         occurrences all number
    8
    1
    6
    2
    3
    Eye disorders
    Eye infection
         subjects affected / exposed
    6 / 98 (6.12%)
    4 / 98 (4.08%)
    5 / 93 (5.38%)
    1 / 43 (2.33%)
    0 / 47 (0.00%)
         occurrences all number
    8
    4
    5
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    25 / 98 (25.51%)
    23 / 98 (23.47%)
    37 / 93 (39.78%)
    11 / 43 (25.58%)
    9 / 47 (19.15%)
         occurrences all number
    27
    26
    46
    14
    9
    Diarrhoea
         subjects affected / exposed
    5 / 98 (5.10%)
    11 / 98 (11.22%)
    24 / 93 (25.81%)
    1 / 43 (2.33%)
    4 / 47 (8.51%)
         occurrences all number
    5
    12
    28
    1
    4
    Gastroenteritis
         subjects affected / exposed
    8 / 98 (8.16%)
    8 / 98 (8.16%)
    8 / 93 (8.60%)
    8 / 43 (18.60%)
    3 / 47 (6.38%)
         occurrences all number
    9
    9
    8
    9
    3
    Nausea
         subjects affected / exposed
    15 / 98 (15.31%)
    21 / 98 (21.43%)
    12 / 93 (12.90%)
    10 / 43 (23.26%)
    11 / 47 (23.40%)
         occurrences all number
    16
    25
    14
    14
    12
    Reflux gastritis
         subjects affected / exposed
    5 / 98 (5.10%)
    7 / 98 (7.14%)
    2 / 93 (2.15%)
    1 / 43 (2.33%)
    3 / 47 (6.38%)
         occurrences all number
    6
    8
    2
    1
    3
    Hepatobiliary disorders
    Liver function test abnormal
         subjects affected / exposed
    17 / 98 (17.35%)
    15 / 98 (15.31%)
    24 / 93 (25.81%)
    6 / 43 (13.95%)
    6 / 47 (12.77%)
         occurrences all number
    22
    19
    25
    6
    8
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    2 / 98 (2.04%)
    9 / 98 (9.18%)
    12 / 93 (12.90%)
    4 / 43 (9.30%)
    5 / 47 (10.64%)
         occurrences all number
    2
    11
    12
    5
    5
    Pruritus
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
    3 / 93 (3.23%)
    3 / 43 (6.98%)
    2 / 47 (4.26%)
         occurrences all number
    0
    1
    3
    3
    2
    Renal and urinary disorders
    Renal impairment
    Additional description: renal insufficiency
         subjects affected / exposed
    1 / 98 (1.02%)
    2 / 98 (2.04%)
    3 / 93 (3.23%)
    0 / 43 (0.00%)
    4 / 47 (8.51%)
         occurrences all number
    1
    2
    4
    0
    6
    Urinary tract infection
         subjects affected / exposed
    6 / 98 (6.12%)
    3 / 98 (3.06%)
    7 / 93 (7.53%)
    0 / 43 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    7
    3
    9
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 98 (15.31%)
    7 / 98 (7.14%)
    12 / 93 (12.90%)
    5 / 43 (11.63%)
    3 / 47 (6.38%)
         occurrences all number
    15
    8
    13
    5
    4
    Arthritis
         subjects affected / exposed
    7 / 98 (7.14%)
    4 / 98 (4.08%)
    4 / 93 (4.30%)
    2 / 43 (4.65%)
    1 / 47 (2.13%)
         occurrences all number
    8
    4
    4
    2
    1
    Osteoarthritis
         subjects affected / exposed
    2 / 98 (2.04%)
    2 / 98 (2.04%)
    6 / 93 (6.45%)
    3 / 43 (6.98%)
    2 / 47 (4.26%)
         occurrences all number
    2
    2
    6
    4
    2
    Back pain
         subjects affected / exposed
    12 / 98 (12.24%)
    19 / 98 (19.39%)
    13 / 93 (13.98%)
    3 / 43 (6.98%)
    9 / 47 (19.15%)
         occurrences all number
    13
    22
    14
    4
    13
    Muscle contractions involuntary
         subjects affected / exposed
    6 / 98 (6.12%)
    5 / 98 (5.10%)
    5 / 93 (5.38%)
    2 / 43 (4.65%)
    4 / 47 (8.51%)
         occurrences all number
    7
    6
    5
    2
    4
    Rotator cuff syndrome
         subjects affected / exposed
    6 / 98 (6.12%)
    0 / 98 (0.00%)
    2 / 93 (2.15%)
    1 / 43 (2.33%)
    1 / 47 (2.13%)
         occurrences all number
    6
    0
    2
    1
    1
    Tendon disorder
         subjects affected / exposed
    5 / 98 (5.10%)
    9 / 98 (9.18%)
    11 / 93 (11.83%)
    5 / 43 (11.63%)
    2 / 47 (4.26%)
         occurrences all number
    5
    9
    12
    5
    3
    Infections and infestations
    Aphthous ulcer
         subjects affected / exposed
    2 / 98 (2.04%)
    3 / 98 (3.06%)
    8 / 93 (8.60%)
    0 / 43 (0.00%)
    5 / 47 (10.64%)
         occurrences all number
    2
    3
    10
    0
    5
    Influenza
         subjects affected / exposed
    5 / 98 (5.10%)
    10 / 98 (10.20%)
    10 / 93 (10.75%)
    2 / 43 (4.65%)
    4 / 47 (8.51%)
         occurrences all number
    6
    10
    10
    3
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    This pragmatic trial rooted in daily practice is an open label trial and no medication adherence is measured. The trial has a superiority design, so the non-superiority from CoBRA Classic and Avant-Garde vs Slim can be stated.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25359382
    http://www.ncbi.nlm.nih.gov/pubmed/25889222
    http://www.ncbi.nlm.nih.gov/pubmed/27432356
    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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