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    Clinical Trial Results:
    Long term clear skin maintenance treatment optimization in patients with moderate to severe chronic plaque psoriasis: A randomized, multicenter, open-label with blinded-assessment, comparative, 52 week study to evaluate the efficacy, safety and tolerability of secukinumab 300 mg s.c.

    Summary
    EudraCT number
    		 2014-005339-15
    Trial protocol
    		 PT   ES   IE   NL   CZ   SK   AT   BE   HU   SE   DE   BG   DK   FI   LV   LT   FR   GR   GB   PL   HR   IT  
    Global end of trial date
    08 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 May 2018
    First version publication date
    20 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAIN457A3302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02409667
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    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
    08 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to demonstrate in the patient pool of PASI 90 responders at Week 24 that secukinumab 300 mg subcutaneous (s.c.) every 6 weeks treatment is non-inferior to secukinumab 300 mg s.c. every 4 weeks treatment with respect to maintaining a PASI 90 response rate at Week 52.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 May 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 22
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    Bulgaria: 50
    Country: Number of subjects enrolled
    Croatia: 20
    Country: Number of subjects enrolled
    Czech Republic: 73
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    Finland: 13
    Country: Number of subjects enrolled
    France: 131
    Country: Number of subjects enrolled
    Germany: 307
    Country: Number of subjects enrolled
    United Kingdom: 50
    Country: Number of subjects enrolled
    Greece: 23
    Country: Number of subjects enrolled
    Hungary: 56
    Country: Number of subjects enrolled
    Israel: 46
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Latvia: 49
    Country: Number of subjects enrolled
    Lithuania: 32
    Country: Number of subjects enrolled
    Netherlands: 43
    Country: Number of subjects enrolled
    Poland: 122
    Country: Number of subjects enrolled
    Portugal: 37
    Country: Number of subjects enrolled
    Russian Federation: 85
    Country: Number of subjects enrolled
    Slovakia: 29
    Country: Number of subjects enrolled
    Spain: 351
    Country: Number of subjects enrolled
    Sweden: 20
    Country: Number of subjects enrolled
    Switzerland: 22
    Worldwide total number of subjects
    1647
    EEA total number of subjects
    1494
    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)
    1553
    From 65 to 84 years
    91
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The screening period was up to 4 weeks and rescreening was allowed for an unlimited number of times. At the Screening Visit, every patient was registered in an Interactive Response Technology and the Investigator ensured that the patient fulfilled all the inclusion/exclusion criteria.

    Period 1
    Period 1 title
    Treatment Period 1 ->Treatment Period 2 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Treatment Period 1: All participants
    Arm description
    		 Participants received secukinumab 300 mg subcutaneous (s.c.) every 4 weeks for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AIN457
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 300 mg subcutaneous (s.c.) every 4 weeks for 24 weeks.

    Arm title
    		 Treatment Period 2: Group 1
    Arm description
    		 Participants with moderate to severe plaque psoriasis who had reached PASI 90 response after 24 weeks of treatment with secukinumab 300 mg s.c. every 4 weeks were treated with Secukinumab 300 mg s.c. from week 24 until Week 52 every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AIN457
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 300 mg subcutanous (s.c.) from week 24 until Week 52 every 4 weeks

    Arm title
    		 Treatment Period 2: Group 2
    Arm description
    		 Participants with moderate to severe plaque psoriasis who had reached PASI 90 response after 24 weeks of treatment with secukinumab 300 mg s.c. every 4 weeks were treated with Secukinumab 300 mg s.c. from week 24 until Week 52 every 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AIN457
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 300 mg subcutanous (s.c.) from week 24 until Week 52 every 6 weeks

    Arm title
    		 Treatment period 2: Group 3
    Arm description
    		 Participants with moderate to severe plaque psoriasis who had reached PASI 75 to <90 response after 24 weeks of treatment with secukinumab 300 mg s.c. every 4 weeks will be treated with Secukinumab 300 mg s.c. from week 24 until Week 52 every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AIN457
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 300 mg subcutanous (s.c.) from week 24 until Week 52 every 4 weeks.

    Arm title
    		 Treatment period 2: Group 4
    Arm description
    		 Participants with moderate to severe plaque psoriasis, who had reached PASI 75 to <90 response after 24 weeks of treatment with secukinumab 300 mg s.c. every 4 weeks, were treated with Secukinumab 300 mg s.c. from week 24 until Week 52 every 2 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AIN457
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 300 mg subcutanous (s.c.) from week 24 until Week 52 every 2 weeks

    Number of subjects in period 1
    		Treatment Period 1: All participants Treatment Period 2: Group 1 Treatment Period 2: Group 2 Treatment period 2: Group 3 Treatment period 2: Group 4
    Started
    1647
    644
    662
    114
    93
    Completed
    1526
    621
    641
    106
    90
    Not completed
    121
    23
    21
    8
    3
         Consent withdrawn by subject
    6
    5
    4
    -
    -
         Physician decision
    4
    -
    -
    -
    -
         Adverse event, non-fatal
    25
    7
    4
    1
    2
         Protocol deviation
    20
    -
    -
    -
    -
         Non-compliance with study treatment
    5
    -
    -
    -
    -
         Pregnancy
    1
    -
    1
    -
    1
         Lost to follow-up
    6
    7
    4
    3
    -
         Withdrawal of informed consent
    6
    -
    -
    -
    -
         Lack of efficacy
    48
    -
    -
    2
    -
         Withdrawal by subject
    -
    4
    5
    2
    -
         Protocol deviation
    -
    -
    3
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period 1 ->Treatment Period 2
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Period 1 ->Treatment Period 2 Total
    Number of subjects
    		 1647 1647
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 1553 1553
        From 65-84 years
    		 91 91
        85 years and over
    		 3 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 43.1 ( 13.38 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 476 476
        Male
    		 1171 1171
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 16 16
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 4 4
        White
    		 1597 1597
        More than one race
    		 0 0
        Unknown or Not Reported
    		 30 30

    End points

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    End points reporting groups
    Reporting group title
    Treatment Period 1: All participants
    Reporting group description
    		 Participants received secukinumab 300 mg subcutaneous (s.c.) every 4 weeks for 24 weeks.

    Reporting group title
    Treatment Period 2: Group 1
    Reporting group description
    		 Participants with moderate to severe plaque psoriasis who had reached PASI 90 response after 24 weeks of treatment with secukinumab 300 mg s.c. every 4 weeks were treated with Secukinumab 300 mg s.c. from week 24 until Week 52 every 4 weeks.

    Reporting group title
    Treatment Period 2: Group 2
    Reporting group description
    		 Participants with moderate to severe plaque psoriasis who had reached PASI 90 response after 24 weeks of treatment with secukinumab 300 mg s.c. every 4 weeks were treated with Secukinumab 300 mg s.c. from week 24 until Week 52 every 6 weeks.

    Reporting group title
    Treatment period 2: Group 3
    Reporting group description
    		 Participants with moderate to severe plaque psoriasis who had reached PASI 75 to <90 response after 24 weeks of treatment with secukinumab 300 mg s.c. every 4 weeks will be treated with Secukinumab 300 mg s.c. from week 24 until Week 52 every 4 weeks.

    Reporting group title
    Treatment period 2: Group 4
    Reporting group description
    		 Participants with moderate to severe plaque psoriasis, who had reached PASI 75 to <90 response after 24 weeks of treatment with secukinumab 300 mg s.c. every 4 weeks, were treated with Secukinumab 300 mg s.c. from week 24 until Week 52 every 2 weeks.

    Primary: Maintenance of PASI 90 response at Week 52 in participants with a PASI 90 response at Week 24

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    End point title
    		 Maintenance of PASI 90 response at Week 52 in participants with a PASI 90 response at Week 24 [1]
    End point description
    PASI is a combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, arms, trunk, legs; each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, erythema, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4).
    End point type
    Primary
    End point timeframe
    Week 52
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 1 and Group 2 at the time of observation.
    End point values
    		 Treatment Period 2: Group 1 Treatment Period 2: Group 2
    Number of subjects analysed
    644
    662
    Units: Participants
    552
    496
    Statistical analysis title
    		 Maintenance of PASI 90
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.1499
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.44
         upper limit
    		 2.55
    Notes
    [2] - The statistical null-hypothesis to be rejected in the primary analysis was that the odds ratio of maintaining a PASI 90 response for patients with secukinumab 4-weekly dosing versus patients on secukinumab 6-weekly dosing exceeds the non-inferiority margin of 1+δ.

    Secondary: Key secondary: PASI 90 response rate at Week 52 in participants with a PASI response of ≥75 to <90 at week 24

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    End point title
    		 Key secondary: PASI 90 response rate at Week 52 in participants with a PASI response of ≥75 to <90 at week 24 [3]
    End point description
    PASI is a combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, arms, trunk, legs; each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, erythema, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4).
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 3 and Group 4 at the time of observation.
    End point values
    		 Treatment period 2: Group 3 Treatment period 2: Group 4
    Number of subjects analysed
    114
    92
    Units: Participants
    53
    52
    Statistical analysis title
    		 PASI 90 rate
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1013
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.1

    Secondary: PASI 50, PASI 75, PASI 100 and IGA mod 2011 0 or 1 responders at Week 52 in participants with a PASI 90 response at Week 24

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    End point title
    		 PASI 50, PASI 75, PASI 100 and IGA mod 2011 0 or 1 responders at Week 52 in participants with a PASI 90 response at Week 24 [4]
    End point description
    PASI is a combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72 (maximal disease). Body is divided into 4 areas for scoring (head, arms, trunk, legs; each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, erythema, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 50, 75, 90 and 100 were defined as participants achieving ≥ 50%, 75%, 90% or 100% improvement from baseline. The IGA mod 2011 scale is static, i.e. it referred exclusively to the participant's disease at the time of the assessment, and did not compare with any of the participant's previous disease states at previous visits. The scores are: 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe.
    End point type
    Secondary
    End point timeframe
    week 52
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 1 and Group 2 at the time of observation.
    End point values
    		 Treatment Period 2: Group 1 Treatment Period 2: Group 2
    Number of subjects analysed
    644
    662
    Units: Participants
        PASI 50 (n=610,629)|
    608
    624
        PASI 75 (n=610,629)|
    597
    588
        PASI 90 (n=610,629)|
    553
    496
        PASI 100 (n=610,629)|
    378
    305
        IGA mod 2011 (n=609,628)|
    564
    529
    No statistical analyses for this end point

    Secondary: PASI 50, PASI 75, PASI 100 and IGA mod 2011 0 or 1 responders at Week 52 in participants with a PASI response of ≥75 to <90 at week 24

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    End point title
    		 PASI 50, PASI 75, PASI 100 and IGA mod 2011 0 or 1 responders at Week 52 in participants with a PASI response of ≥75 to <90 at week 24 [5]
    End point description
    PASI is a combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72 (maximal disease). Body is divided into 4 areas for scoring (head, arms, trunk, legs; each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, erythema, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 50, 75, 90 and 100 were defined as participants achieving ≥ 50%, 75%, 90% or 100% improvement from baseline. The IGA mod 2011 scale is static, i.e. it referred exclusively to the participant's disease at the time of the assessment, and did not compare with any of the participant's previous disease states at previous visits. The scores are: 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 3 and Group 4 at the time of observation.
    End point values
    		 Treatment period 2: Group 3 Treatment period 2: Group 4
    Number of subjects analysed
    104
    90
    Units: Participants
        PASI 50|
    98
    88
        PASI 75|
    74
    80
        PASI 90|
    53
    52
        PASI 100|
    12
    13
        IGA mod 2011 0 or 1|
    64
    72
    No statistical analyses for this end point

    Secondary: Change from baseline in PASI in participants with a PASI 90 response at Week 24

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    End point title
    		 Change from baseline in PASI in participants with a PASI 90 response at Week 24 [6]
    End point description
    PASI is a combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, arms, trunk, legs; each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, erythema, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Weeks 28, 32, 36, 40, 44, 48 and 52
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 1 and Group 2 at the time of observation.
    End point values
    		 Treatment Period 2: Group 1 Treatment Period 2: Group 2
    Number of subjects analysed
    644
    662
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 28 (n=642,656)|
    -20.7 ( 8.471 )
    -19.9 ( 8.511 )
        Week 32 (n=638,655)|
    -20.7 ( 8.581 )
    -19.8 ( 8.474 )
        Week 36 (n=638,650)|
    -20.6 ( 8.439 )
    -19.7 ( 8.563 )
        Week 40 (n=632,649)|
    -20.5 ( 8.392 )
    -19.6 ( 8.393 )
        Week 44 (n=623,639)|
    -20.5 ( 8.384 )
    -19.6 ( 8.484 )
        Week 48 (n=625,638)|
    -20.5 ( 8.472 )
    -19.2 ( 8.509 )
        Week 52 (n=610,629)|
    -20.4 ( 8.301 )
    -19.2 ( 8.513 )
    Statistical analysis title
    		 Change from baseline in PASI, week 28
    Statistical analysis description
    Week 28
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0489
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean (LSM) estimate
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0
    Statistical analysis title
    		 Change from baseline in PASI, week 32
    Statistical analysis description
    Week 32
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1073
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0.02
    Statistical analysis title
    		 Change from baseline in PASI, week 36
    Statistical analysis description
    Week 36
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 -0.12
    Statistical analysis title
    		 Change from baseline in PASI, week 40
    Statistical analysis description
    Week 40
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0005
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 -0.11
    Statistical analysis title
    		 Change from baseline in PASI, week 44
    Statistical analysis description
    Week 44
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 -0.15
    Statistical analysis title
    		 Change from baseline in PASI, week 48
    Statistical analysis description
    Week 48
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.27
    Statistical analysis title
    		 Change from baseline in PASI, week 52
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0
    Method
    		 ANCOVA
    Parameter type
    		 LSM mean
    Point estimate
    -0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 -0.36

    Secondary: Change from baseline in PASI in participants with a PASI response of ≥75 to <90 at week 24

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    End point title
    		 Change from baseline in PASI in participants with a PASI response of ≥75 to <90 at week 24 [7]
    End point description
    PASI is a combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, arms, trunk, legs; each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, erythema, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Weeks 28, 32, 36, 40, 44, 48 and 52
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 3 and Group 4 at the time of observation.
    End point values
    		 Treatment period 2: Group 3 Treatment period 2: Group 4
    Number of subjects analysed
    114
    92
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 28 (n=114,92)|
    -16.1 ( 6.160 )
    -16.3 ( 8.029 )
        Week 32 (n=112,91)|
    -15.9 ( 6.002 )
    -16.6 ( 7.941 )
        Week 36 (n=111,92)|
    -16.1 ( 6.356 )
    -16.6 ( 7.996 )
        Week 40 (n=111,90)|
    -16.1 ( 6.908 )
    -16.8 ( 8.170 )
        Week 44 (n=108,89)|
    -16.1 ( 6.553 )
    -16.6 ( 8.259 )
        Week 48 (n=109,90)|
    -15.6 ( 6.246 )
    -16.8 ( 8.307 )
        Week 52 (n=104,90)|
    -15.5 ( 6.371 )
    -16.6 ( 8.011 )
    Statistical analysis title
    		 Change from baseline in PASI, week 28
    Statistical analysis description
    Week 28
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.174
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.99
    Statistical analysis title
    		 Change from baseline in PASI, week 32
    Statistical analysis description
    Week 32
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0287
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.08
         upper limit
    		 1.5
    Statistical analysis title
    		 Change from baseline in PASI, week 36
    Statistical analysis description
    Week 36
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1202
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 1.41
    Statistical analysis title
    		 Change from baseline in PASI, week 40
    Statistical analysis description
    Week 40
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1157
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 1.68
    Statistical analysis title
    		 Change from baseline in PASI, week 44
    Statistical analysis description
    Week 44
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3189
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 1.59
    Statistical analysis title
    		 Change from baseline in PASI, week 48
    Statistical analysis description
    Week 48
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.024
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 2.18
    Statistical analysis title
    		 Change from baseline in PASI, week 52
    Statistical analysis description
    Week 52
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.009
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 2.57

    Secondary: Change from baseline in DLQI in participants with a PASI 90 response at Week 24

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    End point title
    		 Change from baseline in DLQI in participants with a PASI 90 response at Week 24 [8]
    End point description
    The DLQI is a ten item general dermatology disability index designed to assess health-related quality of life in adult participants with skin diseases such as eczema, psoriasis, acne and viral worts. It is a self-administered questionnaire which includes domains of daily activity, leisure, personal relationships, symptoms and feelings, treatment and school/work activities. Each domain has 4 response categories ranging from 0 (not at all) to 3 (very much). "Not relevant" is a valid score also and is scored as 0. The DLQI total score is a sum of all 10 responses. Scores range from 0 to 30 with higher scores indicating greater health-related quality of life impairment. A negative mean percentage change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 1 and Group 2 at the time of observation.
    End point values
    		 Treatment Period 2: Group 1 Treatment Period 2: Group 2
    Number of subjects analysed
    605
    624
    Units: score on a scale
        arithmetic mean (standard deviation)
    -12.7 ( 7.325 )
    -11.4 ( 7.480 )
    Statistical analysis title
    		 Change from baseline in DLQI
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.93
         upper limit
    		 -0.31

    Secondary: Change from baseline in DLQI in participants with a PASI response of ≥75 to <90 at week 24

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    End point title
    		 Change from baseline in DLQI in participants with a PASI response of ≥75 to <90 at week 24 [9]
    End point description
    The DLQI is a ten item general dermatology disability index designed to assess health-related quality of life in adult participants with skin diseases such as eczema, psoriasis, acne and viral worts. It is a self-administered questionnaire which includes domains of daily activity, leisure, personal relationships, symptoms and feelings, treatment and school/work activities. Each domain has 4 response categories ranging from 0 (not at all) to 3 (very much). "Not relevant" is a valid score also and is scored as 0. The DLQI total score is a sum of all 10 responses. Scores range from 0 to 30 with higher scores indicating greater health-related quality of life impairment. A negative mean percentage change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 3 and Group 4 at the time of observation.
    End point values
    		 Treatment period 2: Group 3 Treatment period 2: Group 4
    Number of subjects analysed
    105
    89
    Units: score on a scale
        arithmetic mean (standard deviation)
    -10.0 ( 6.605 )
    -9.72 ( 6.880 )
    Statistical analysis title
    		 Change from baseline in DLQI
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0675
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 2.42

    Secondary: Change from baseline in Work Productivity and Activity Impairment Questionnaire - Psoriasis (WPAI-PSO) score in participants with a PASI 90 response at Week 24

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    End point title
    		 Change from baseline in Work Productivity and Activity Impairment Questionnaire - Psoriasis (WPAI-PSO) score in participants with a PASI 90 response at Week 24 [10]
    End point description
    The WPAI-PSO is a self-administered questionnaire comprised of 6 questions about effects of psoriasis on the patient’s ability to work and perform regular activities based on the previous 7 days. The questionnaire quantifies the number of hours the respondent was unable to work and evaluates how much the respondent’s psoriasis affected productivity while working. For respondents who were not in paid employment, the questionnaire evaluated how much the respondent’s psoriasis affects their ability to perform regular daily activities. Four outcomes were generated from the WPAI-PSO: % Absenteeism: percent work time missed due to health; % Presenteism: percent impairment while working due to health; % Total work productivity impairment: percent overall work impairment due to health; % Total activity impairment: percent activity impairment due to health for all respondents. First 3 outcomes applied to employed participants only. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 1 and Group 2 at the time of observation.
    End point values
    		 Treatment Period 2: Group 1 Treatment Period 2: Group 2
    Number of subjects analysed
    644
    662
    Units: score on a scale
    arithmetic mean (standard deviation)
        Absenteeism (n=360,356)|
    -4.70 ( 19.590 )
    -1.99 ( 19.759 )
        Presenteeism (n=351,348)|
    -23.1 ( 25.968 )
    -23.0 ( 26.522 )
        Total activity impairment (n=320,312)|
    -24.3 ( 27.850 )
    -23.2 ( 29.861 )
        Work productivity loss (n=546,550)|
    -31.9 ( 29.392 )
    -28.6 ( 27.996 )
    Statistical analysis title
    		 Change in WPAI
    Statistical analysis description
    Absenteeism
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2101
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.48
         upper limit
    		 0.55
    Statistical analysis title
    		 Change in WPAI
    Statistical analysis description
    Presenteeism
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2971
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.93
         upper limit
    		 0.59
    Statistical analysis title
    		 Change in WPAI
    Statistical analysis description
    Total activity impairment
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5499
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.59
         upper limit
    		 1.38
    Statistical analysis title
    		 Change in WPAI
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0758
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.28
         upper limit
    		 0.11

    Secondary: Change from baseline in WPAI-PSO score in participants with a PASI response of ≥75 to <90 at week 24

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    End point title
    		 Change from baseline in WPAI-PSO score in participants with a PASI response of ≥75 to <90 at week 24 [11]
    End point description
    The WPAI-PSO is a self-administered questionnaire comprised of 6 questions about effects of psoriasis on the patient’s ability to work and perform regular activities based on the previous 7 days. The questionnaire quantifies the number of hours the respondent was unable to work and evaluates how much the respondent’s psoriasis affected productivity while working. For respondents who were not in paid employment, the questionnaire evaluated how much the respondent’s psoriasis affects their ability to perform regular daily activities. Four outcomes were generated from the WPAI-PSO: % Absenteeism: percent work time missed due to health; % Presenteism: percent impairment while working due to health; % Total work productivity impairment: percent overall work impairment due to health; % Total activity impairment: percent activity impairment due to health for all respondents. First 3 outcomes applied to employed participants only. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 3 and Group 4 at the time of observation.
    End point values
    		 Treatment period 2: Group 3 Treatment period 2: Group 4
    Number of subjects analysed
    114
    92
    Units: score on a scale
    arithmetic mean (standard deviation)
        Absenteeism (n=54,49)|
    -2.36 ( 12.990 )
    -3.45 ( 18.698 )
        Presenteeism (n=52,48)|
    -22.9 ( 28.377 )
    -22.1 ( 26.333 )
        Total activity impairment (n=46,43)|
    -23.1 ( 28.657 )
    -21.7 ( 29.905 )
        Work productivity loss (n=89,77)|
    -18.2 ( 28.824 )
    -22.5 ( 25.192 )
    Statistical analysis title
    		 Change in WPAI-PSO
    Statistical analysis description
    Absenteeism
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4156
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.71
         upper limit
    		 4.11
    Statistical analysis title
    		 Change in WPAI-PSO
    Statistical analysis description
    Presenteeism
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8619
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.59
         upper limit
    		 7.85
    Statistical analysis title
    		 Change in WPAI-PSO
    Statistical analysis description
    Total activity impairment
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6139
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.31
         upper limit
    		 10.61
    Statistical analysis title
    		 Change in WPAI-PSO
    Statistical analysis description
    Work productivity loss
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5674
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.16
         upper limit
    		 7.56

    Secondary: Change from baseline in pain, itching and scaling score in participants with a PASI 90 response at Week 24

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    End point title
    		 Change from baseline in pain, itching and scaling score in participants with a PASI 90 response at Week 24 [12]
    End point description
    Self-administered, 11-point numeric rating scales (NRS, 0-10) were used to evaluate the patients’ assessment of their current pain, itching and scaling. Respondents answered the following questions for the assessment: Pain: Overall, how severe was your psoriasis-related pain over the past 24 hours?; Itching: Overall, how severe was your psoriasis-related itch over the past 24 hours?; and Scaling: Overall, how severe was your psoriasis-related scaling over the past 24 hours? Patients had to rate their pain, itching, and scaling from 0 to 10 (11-point scale), with the understanding that the 0 represents the absence or null end of the pain, itching, or scale intensity (i.e. no pain, itching or scaling) and the 10 represents the other extreme of pain, itching, or scaling intensity (i.e. pain, itching or scaling as bad as it could be). The number that the patient selected represents his or her intensity score in the respective category. A negative change from baseline indicates improvement
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 1 and Group 2 at the time of observation.
    End point values
    		 Treatment Period 2: Group 1 Treatment Period 2: Group 2
    Number of subjects analysed
    644
    662
    Units: score on a scale
    arithmetic mean (standard deviation)
        Pain (n=495,478)|
    -4.56 ( 2.771 )
    -4.17 ( 2.2727 )
        Itching (n=590,608)|
    -5.59 ( 2.885 )
    -5.20 ( 2.985 )
        Scaling (n=598,610)|
    -6.05 ( 2.659 )
    -5.73 ( 2.757 )
    Statistical analysis title
    		 Change in pain score
    Statistical analysis description
    Pain
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1219
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.04
    Statistical analysis title
    		 Change in itching score
    Statistical analysis description
    Itching
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 -0.18
    Statistical analysis title
    		 Change in scaling score
    Statistical analysis description
    Scaling
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0003
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 -0.14

    Secondary: Change from baseline in pain, itching and scaling score in participants with a PASI response of ≥75 to <90 at week 24

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    End point title
    		 Change from baseline in pain, itching and scaling score in participants with a PASI response of ≥75 to <90 at week 24 [13]
    End point description
    Self-administered, 11-point numeric rating scales (NRS, 0-10) were used to evaluate the patients’ assessment of their current pain, itching and scaling. Respondents answered the following questions for the assessment: Pain: Overall, how severe was your psoriasis-related pain over the past 24 hours?; Itching: Overall, how severe was your psoriasis-related itch over the past 24 hours?; and Scaling: Overall, how severe was your psoriasis-related scaling over the past 24 hours? Patients had to rate their pain, itching, and scaling from 0 to 10 (11-point scale), with the understanding that the 0 represents the absence or null end of the pain, itching, or scale intensity (i.e. no pain, itching or scaling) and the 10 represents the other extreme of pain, itching, or scaling intensity (i.e. pain, itching or scaling as bad as it could be). The number that the patient selected represents his or her intensity score in the respective category. A negative change from baseline indicates improvement
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 3 and Group 4 at the time of observation.
    End point values
    		 Treatment period 2: Group 3 Treatment period 2: Group 4
    Number of subjects analysed
    114
    92
    Units: score on a scale
    arithmetic mean (standard deviation)
        Pain (n=80,68)|
    -3.59 ( 2.754 )
    -3.68 ( 3.049 )
        Itching (n=101,83)|
    -4.13 ( 2.883 )
    -4.49 ( 3.129 )
        Scaling (n=102,89)|
    -4.66 ( 2.960 )
    -5.40 ( 2.899 )
    Statistical analysis title
    		 Change in pain score
    Statistical analysis description
    Pain
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6457
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 0.92
    Statistical analysis title
    		 Change in itching score
    Statistical analysis description
    Itching
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6136
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 0.94
    Statistical analysis title
    		 Change in scaling score
    Statistical analysis description
    Scaling
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0203
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 1.39

    Secondary: Change from baseline in the European Quality of Life - 5 Dimensions (EQ-5D) visual analogue scale (VAS) in participants with a PASI 90 response at Week 24

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    End point title
    		 Change from baseline in the European Quality of Life - 5 Dimensions (EQ-5D) visual analogue scale (VAS) in participants with a PASI 90 response at Week 24 [14]
    End point description
    A visual analogue scale (VAS) was used within the EQ-5D. This scale recorded the respondent’s self-rated health on a vertical 20-cm VAS where the endpoints were labeled “best imaginable health state” and “worst imaginable health state.” This resulted in a numeric value set ranging from 0 (=”worst imaginable health state”) up to 100 (=”best imaginable health state”). A positive change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 1 and Group 2 at the time of observation.
    End point values
    		 Treatment Period 2: Group 1 Treatment Period 2: Group 2
    Number of subjects analysed
    603
    620
    Units: score on a scale
        arithmetic mean (standard deviation)
    24.34 ( 23.296 )
    21.24 ( 22.074 )
    Statistical analysis title
    		 Change in EQ-5D VAS
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1223
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0027
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    2.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 3.68

    Secondary: Change from baseline in the EQ-5D VAS in participants with a PASI response of ≥75 to <90 at week 24

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    End point title
    		 Change from baseline in the EQ-5D VAS in participants with a PASI response of ≥75 to <90 at week 24 [15]
    End point description
    A visual analogue scale (VAS) was used within the EQ-5D. This scale recorded the respondent’s self-rated health on a vertical 20-cm VAS where the endpoints were labeled “best imaginable health state” and “worst imaginable health state.” This resulted in a numeric value set ranging from 0 (=”worst imaginable health state”) up to 100 (=”best imaginable health state”).
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 3 and Group 4 at the time of observation.
    End point values
    		 Treatment period 2: Group 3 Treatment period 2: Group 4
    Number of subjects analysed
    103
    88
    Units: score on a scale
        arithmetic mean (standard deviation)
    15.86 ( 20.099 )
    18.92 ( 19.855 )
    Statistical analysis title
    		 Change in EQ-5D VAS
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2823
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -2.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.55
         upper limit
    		 1.92

    Secondary: Change from baseline in the EQ-5D utility index (Germany, United Kingdom (UK)) in participants with a PASI 90 response at Week 24

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    End point title
    		 Change from baseline in the EQ-5D utility index (Germany, United Kingdom (UK)) in participants with a PASI 90 response at Week 24 [16]
    End point description
    The EQ-5D quantifies the health state of a patient for the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. In the current study the EQ-5D-5L version has been used which evaluates each of these dimensions using the following five labels: “no problems”, “slight problems”, “moderate problems”, “severe problems” and “unable to/extreme problems”. Based on the five dimensions, a summary score (utility index) was derived using country specific value sets evaluating the patient condition described by the outcome in the single dimensions. For this trial, the EQ-5D-5L utility index based on the crosswalk value sets available from the EuroQol for Germany and for UK (https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/) was calculated. A positive change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 1 and Group 2 at the time of observation.
    End point values
    		 Treatment Period 2: Group 1 Treatment Period 2: Group 2
    Number of subjects analysed
    605
    623
    Units: score on a scale
    arithmetic mean (standard deviation)
        Germany|
    0.17 ( 0.200 )
    0.13 ( 0.182 )
        UK|
    0.28 ( 0.250 )
    0.22 ( 0.230 )
    Statistical analysis title
    		 Change in EQ-5D utility index
    Statistical analysis description
    Germany
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1228
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0861
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.02
    Statistical analysis title
    		 Change in EQ-5D utitlity index
    Statistical analysis description
    UK
    Comparison groups
    Treatment Period 2: Group 1 v Treatment Period 2: Group 2
    Number of subjects included in analysis
    1228
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0117
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.04

    Secondary: Change from baseline in the EQ-5D utility index (Germany, UK) in participants with a PASI response of ≥75 to <90 at week 24

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    End point title
    		 Change from baseline in the EQ-5D utility index (Germany, UK) in participants with a PASI response of ≥75 to <90 at week 24 [17]
    End point description
    The EQ-5D quantifies the health state of a patient for the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. In the current study the EQ-5D-5L version has been used which evaluates each of these dimensions using the following five labels: “no problems”, “slight problems”, “moderate problems”, “severe problems” and “unable to/extreme problems”. Based on the five dimensions, a summary score (utility index) was derived using country specific value sets evaluating the patient condition described by the outcome in the single dimensions. For this trial, the EQ-5D-5L utility index based on the crosswalk value sets available from the EuroQol for Germany and for UK (https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/) was calculated.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applies to Group 3 and Group 4 at the time of observation.
    End point values
    		 Treatment period 2: Group 3 Treatment period 2: Group 4
    Number of subjects analysed
    103
    89
    Units: score on a scale
    arithmetic mean (standard deviation)
        Germany|
    0.11 ( 0.164 )
    0.13 ( 0.164 )
        UK|
    0.18 ( 0.206 )
    0.21 ( 0.204 )
    Statistical analysis title
    		 Change in EQ-5D utitlity index
    Statistical analysis description
    Germany
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1852
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.01
    Statistical analysis title
    		 Change in EQ-5D utitlity index
    Statistical analysis description
    UK
    Comparison groups
    Treatment period 2: Group 3 v Treatment period 2: Group 4
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2203
    Method
    		 ANCOVA
    Parameter type
    		 LSM estimate
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.02

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events are monitored from date of First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All other adverse events are monitored from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    The Adverse Events (AE) dataset has MedDRA version 19.1 (5345 records) and 20.0 (1272 records). Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally relat
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    SAF-TP2: Group 1
    Reporting group description
    		 SAF-TP2: Group 1

    Reporting group title
    SAF-TP1: Total
    Reporting group description
    		 SAF-TP1: Total

    Reporting group title
    SAF-TP2: Group 3
    Reporting group description
    		 SAF-TP2: Group 3

    Reporting group title
    SAF-TP2: Group 4
    Reporting group description
    		 SAF-TP2: Group 4

    Reporting group title
    SAF-TP2: Group 2
    Reporting group description
    		 SAF-TP2: Group 2

    Serious adverse events
    		 SAF-TP2: Group 1 SAF-TP1: Total SAF-TP2: Group 3 SAF-TP2: Group 4 SAF-TP2: Group 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 644 (3.88%)
    73 / 1647 (4.43%)
    4 / 114 (3.51%)
    3 / 93 (3.23%)
    25 / 662 (3.78%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Basal cell carcinoma
         subjects affected / exposed
    1 / 644 (0.16%)
    2 / 1647 (0.12%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 644 (0.00%)
    2 / 1647 (0.12%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Gastric cancer stage II
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Malignant melanoma
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Oral fibroma
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Plasma cell myeloma
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Skin cancer
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Thyroid adenoma
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Deep vein thrombosis
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    1 / 93 (1.08%)
    0 / 662 (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
    Iliac artery occlusion
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Pregnancy, puerperium and perinatal conditions
    Ectopic pregnancy
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Oedema peripheral
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Social circumstances
    Alcohol use
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Reproductive system and breast disorders
    Breast enlargement
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Peyronie's disease
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Prostatitis
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    1 / 114 (0.88%)
    0 / 93 (0.00%)
    0 / 662 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Nasal polyps
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Anxiety disorder
         subjects affected / exposed
    1 / 644 (0.16%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Confusional state
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Depression
         subjects affected / exposed
    0 / 644 (0.00%)
    2 / 1647 (0.12%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 644 (0.16%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 644 (0.16%)
    9 / 1647 (0.55%)
    1 / 114 (0.88%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 9
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 644 (0.31%)
    10 / 1647 (0.61%)
    1 / 114 (0.88%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 10
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 644 (0.00%)
    3 / 1647 (0.18%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Transaminases increased
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 644 (0.00%)
    2 / 1647 (0.12%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Bone contusion
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Clavicle fracture
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Fracture
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Joint dislocation
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    2 / 662 (0.30%)
         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
    Joint injury
         subjects affected / exposed
    0 / 644 (0.00%)
    2 / 1647 (0.12%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Ligament rupture
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Meniscus injury
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Radius fracture
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Spinal column injury
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Tendon rupture
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Thermal burn
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Tibia fracture
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    1 / 114 (0.88%)
    0 / 93 (0.00%)
    0 / 662 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    2 / 662 (0.30%)
         occurrences causally related to treatment / all
    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
    Atrial flutter
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Coronary artery disease
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Coronary artery stenosis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    1 / 114 (0.88%)
    0 / 93 (0.00%)
    0 / 662 (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
    Myocardial ischaemia
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Cerebral ischaemia
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 644 (0.00%)
    2 / 1647 (0.12%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Epilepsy
         subjects affected / exposed
    1 / 644 (0.16%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial nerve disorder
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Monoplegia
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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 sensorimotor neuropathy
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    1 / 93 (1.08%)
    0 / 662 (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
    Seizure
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Tension headache
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Colitis ulcerative
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Crohn's disease
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Haematochezia
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Haemorrhoids
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Inguinal hernia
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Intestinal polyp
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Pancreatitis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Hepatobiliary disorders
    Alcoholic liver disease
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    1 / 114 (0.88%)
    0 / 93 (0.00%)
    0 / 662 (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
    Bile duct stone
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Biliary colic
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Cholecystitis acute
         subjects affected / exposed
    1 / 644 (0.16%)
    2 / 1647 (0.12%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 644 (0.16%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Hepatic function abnormal
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Hepatotoxicity
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Dermatitis exfoliative
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Lichenoid keratosis
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Skin exfoliation
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Renal and urinary disorders
    Calculus urethral
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Renal colic
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Renal failure
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Ureteric stenosis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Bursitis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 644 (0.00%)
    3 / 1647 (0.18%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    1 / 114 (0.88%)
    0 / 93 (0.00%)
    0 / 662 (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
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Appendicitis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Endocarditis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Erysipelas
         subjects affected / exposed
    0 / 644 (0.00%)
    2 / 1647 (0.12%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Giardiasis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Herpes zoster
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Infectious mononucleosis
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Osteomyelitis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Pilonidal cyst
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Pneumonia
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Pneumonia bacterial
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Respiratory tract infection
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    1 / 93 (1.08%)
    0 / 662 (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
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Tonsillitis
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    1 / 662 (0.15%)
         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
    Urinary tract infection
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    1 / 114 (0.88%)
    0 / 93 (0.00%)
    0 / 662 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 1647 (0.06%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Viral infection
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 1647 (0.00%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (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
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 644 (0.00%)
    2 / 1647 (0.12%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    0 / 662 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    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: 2%
    Non-serious adverse events
    		 SAF-TP2: Group 1 SAF-TP1: Total SAF-TP2: Group 3 SAF-TP2: Group 4 SAF-TP2: Group 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    272 / 644 (42.24%)
    884 / 1647 (53.67%)
    64 / 114 (56.14%)
    60 / 93 (64.52%)
    288 / 662 (43.50%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 644 (0.62%)
    10 / 1647 (0.61%)
    2 / 114 (1.75%)
    4 / 93 (4.30%)
    6 / 662 (0.91%)
         occurrences all number
    4
    10
    2
    4
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 644 (0.62%)
    8 / 1647 (0.49%)
    1 / 114 (0.88%)
    3 / 93 (3.23%)
    3 / 662 (0.45%)
         occurrences all number
    4
    8
    1
    3
    3
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    4 / 644 (0.62%)
    3 / 1647 (0.18%)
    0 / 114 (0.00%)
    2 / 93 (2.15%)
    4 / 662 (0.60%)
         occurrences all number
    4
    3
    0
    2
    4
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 644 (1.09%)
    55 / 1647 (3.34%)
    4 / 114 (3.51%)
    4 / 93 (4.30%)
    10 / 662 (1.51%)
         occurrences all number
    7
    56
    5
    4
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    31 / 644 (4.81%)
    141 / 1647 (8.56%)
    6 / 114 (5.26%)
    1 / 93 (1.08%)
    27 / 662 (4.08%)
         occurrences all number
    38
    214
    7
    1
    56
    Migraine
         subjects affected / exposed
    1 / 644 (0.16%)
    9 / 1647 (0.55%)
    0 / 114 (0.00%)
    2 / 93 (2.15%)
    1 / 662 (0.15%)
         occurrences all number
    1
    13
    0
    2
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 644 (0.78%)
    41 / 1647 (2.49%)
    0 / 114 (0.00%)
    0 / 93 (0.00%)
    2 / 662 (0.30%)
         occurrences all number
    5
    48
    0
    0
    2
    Injection site haematoma
         subjects affected / exposed
    2 / 644 (0.31%)
    18 / 1647 (1.09%)
    0 / 114 (0.00%)
    2 / 93 (2.15%)
    1 / 662 (0.15%)
         occurrences all number
    3
    21
    0
    3
    1
    Pyrexia
         subjects affected / exposed
    10 / 644 (1.55%)
    36 / 1647 (2.19%)
    2 / 114 (1.75%)
    1 / 93 (1.08%)
    8 / 662 (1.21%)
         occurrences all number
    11
    37
    4
    1
    11
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 644 (0.31%)
    4 / 1647 (0.24%)
    1 / 114 (0.88%)
    2 / 93 (2.15%)
    2 / 662 (0.30%)
         occurrences all number
    2
    4
    1
    2
    2
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    3 / 644 (0.47%)
    6 / 1647 (0.36%)
    1 / 114 (0.88%)
    2 / 93 (2.15%)
    0 / 662 (0.00%)
         occurrences all number
    3
    7
    1
    2
    0
    Eye pruritus
         subjects affected / exposed
    0 / 644 (0.00%)
    5 / 1647 (0.30%)
    0 / 114 (0.00%)
    3 / 93 (3.23%)
    0 / 662 (0.00%)
         occurrences all number
    0
    5
    0
    3
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    16 / 644 (2.48%)
    74 / 1647 (4.49%)
    4 / 114 (3.51%)
    0 / 93 (0.00%)
    22 / 662 (3.32%)
         occurrences all number
    18
    85
    4
    0
    22
    Odynophagia
         subjects affected / exposed
    4 / 644 (0.62%)
    7 / 1647 (0.43%)
    1 / 114 (0.88%)
    3 / 93 (3.23%)
    6 / 662 (0.91%)
         occurrences all number
    4
    9
    1
    3
    7
    Toothache
         subjects affected / exposed
    11 / 644 (1.71%)
    34 / 1647 (2.06%)
    3 / 114 (2.63%)
    1 / 93 (1.08%)
    11 / 662 (1.66%)
         occurrences all number
    11
    37
    3
    1
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 644 (1.71%)
    61 / 1647 (3.70%)
    3 / 114 (2.63%)
    0 / 93 (0.00%)
    10 / 662 (1.51%)
         occurrences all number
    11
    64
    3
    0
    10
    Oropharyngeal pain
         subjects affected / exposed
    13 / 644 (2.02%)
    46 / 1647 (2.79%)
    3 / 114 (2.63%)
    1 / 93 (1.08%)
    17 / 662 (2.57%)
         occurrences all number
    13
    52
    3
    1
    19
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    2 / 644 (0.31%)
    3 / 1647 (0.18%)
    0 / 114 (0.00%)
    2 / 93 (2.15%)
    1 / 662 (0.15%)
         occurrences all number
    3
    3
    0
    2
    2
    Dermatitis contact
         subjects affected / exposed
    4 / 644 (0.62%)
    9 / 1647 (0.55%)
    0 / 114 (0.00%)
    3 / 93 (3.23%)
    1 / 662 (0.15%)
         occurrences all number
    4
    9
    0
    3
    1
    Eczema
         subjects affected / exposed
    8 / 644 (1.24%)
    20 / 1647 (1.21%)
    3 / 114 (2.63%)
    1 / 93 (1.08%)
    14 / 662 (2.11%)
         occurrences all number
    11
    24
    3
    2
    17
    Erythrodermic psoriasis
         subjects affected / exposed
    0 / 644 (0.00%)
    0 / 1647 (0.00%)
    3 / 114 (2.63%)
    1 / 93 (1.08%)
    0 / 662 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    Pruritus
         subjects affected / exposed
    9 / 644 (1.40%)
    65 / 1647 (3.95%)
    2 / 114 (1.75%)
    4 / 93 (4.30%)
    11 / 662 (1.66%)
         occurrences all number
    9
    71
    2
    5
    11
    Psoriasis
         subjects affected / exposed
    12 / 644 (1.86%)
    21 / 1647 (1.28%)
    11 / 114 (9.65%)
    8 / 93 (8.60%)
    16 / 662 (2.42%)
         occurrences all number
    12
    22
    11
    8
    16
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 644 (2.48%)
    50 / 1647 (3.04%)
    3 / 114 (2.63%)
    4 / 93 (4.30%)
    19 / 662 (2.87%)
         occurrences all number
    17
    54
    3
    4
    23
    Arthritis
         subjects affected / exposed
    1 / 644 (0.16%)
    4 / 1647 (0.24%)
    0 / 114 (0.00%)
    2 / 93 (2.15%)
    1 / 662 (0.15%)
         occurrences all number
    1
    4
    0
    2
    1
    Back pain
         subjects affected / exposed
    18 / 644 (2.80%)
    64 / 1647 (3.89%)
    4 / 114 (3.51%)
    1 / 93 (1.08%)
    28 / 662 (4.23%)
         occurrences all number
    20
    73
    4
    1
    32
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    12 / 644 (1.86%)
    23 / 1647 (1.40%)
    1 / 114 (0.88%)
    3 / 93 (3.23%)
    6 / 662 (0.91%)
         occurrences all number
    12
    26
    1
    3
    8
    Cystitis
         subjects affected / exposed
    3 / 644 (0.47%)
    12 / 1647 (0.73%)
    0 / 114 (0.00%)
    2 / 93 (2.15%)
    3 / 662 (0.45%)
         occurrences all number
    3
    14
    0
    7
    3
    Folliculitis
         subjects affected / exposed
    8 / 644 (1.24%)
    31 / 1647 (1.88%)
    1 / 114 (0.88%)
    2 / 93 (2.15%)
    8 / 662 (1.21%)
         occurrences all number
    8
    35
    1
    2
    8
    Gastroenteritis
         subjects affected / exposed
    10 / 644 (1.55%)
    22 / 1647 (1.34%)
    3 / 114 (2.63%)
    2 / 93 (2.15%)
    10 / 662 (1.51%)
         occurrences all number
    10
    22
    4
    2
    10
    Influenza
         subjects affected / exposed
    17 / 644 (2.64%)
    36 / 1647 (2.19%)
    4 / 114 (3.51%)
    4 / 93 (4.30%)
    19 / 662 (2.87%)
         occurrences all number
    17
    39
    4
    4
    20
    Nasopharyngitis
         subjects affected / exposed
    3 / 644 (0.47%)
    6 / 1647 (0.36%)
    0 / 114 (0.00%)
    2 / 93 (2.15%)
    6 / 662 (0.91%)
         occurrences all number
    3
    6
    0
    2
    6
    Oral candidiasis
         subjects affected / exposed
    9 / 644 (1.40%)
    25 / 1647 (1.52%)
    0 / 114 (0.00%)
    3 / 93 (3.23%)
    14 / 662 (2.11%)
         occurrences all number
    9
    28
    0
    4
    16
    Oral herpes
         subjects affected / exposed
    12 / 644 (1.86%)
    41 / 1647 (2.49%)
    3 / 114 (2.63%)
    0 / 93 (0.00%)
    8 / 662 (1.21%)
         occurrences all number
    16
    50
    3
    0
    9
    Pulpitis dental
         subjects affected / exposed
    1 / 644 (0.16%)
    4 / 1647 (0.24%)
    2 / 114 (1.75%)
    2 / 93 (2.15%)
    2 / 662 (0.30%)
         occurrences all number
    1
    4
    3
    2
    2
    Rhinitis
         subjects affected / exposed
    8 / 644 (1.24%)
    52 / 1647 (3.16%)
    3 / 114 (2.63%)
    0 / 93 (0.00%)
    12 / 662 (1.81%)
         occurrences all number
    8
    57
    3
    0
    14
    Sinusitis
         subjects affected / exposed
    8 / 644 (1.24%)
    22 / 1647 (1.34%)
    1 / 114 (0.88%)
    2 / 93 (2.15%)
    6 / 662 (0.91%)
         occurrences all number
    9
    23
    1
    2
    7
    Tonsillitis
         subjects affected / exposed
    8 / 644 (1.24%)
    34 / 1647 (2.06%)
    2 / 114 (1.75%)
    3 / 93 (3.23%)
    9 / 662 (1.36%)
         occurrences all number
    8
    36
    2
    4
    11
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 644 (2.80%)
    65 / 1647 (3.95%)
    7 / 114 (6.14%)
    5 / 93 (5.38%)
    16 / 662 (2.42%)
         occurrences all number
    20
    73
    7
    5
    17
    Urinary tract infection
         subjects affected / exposed
    16 / 644 (2.48%)
    26 / 1647 (1.58%)
    3 / 114 (2.63%)
    3 / 93 (3.23%)
    8 / 662 (1.21%)
         occurrences all number
    18
    29
    3
    3
    11
    Viral upper respiratory tract infection
         subjects affected / exposed
    94 / 644 (14.60%)
    368 / 1647 (22.34%)
    23 / 114 (20.18%)
    22 / 93 (23.66%)
    95 / 662 (14.35%)
         occurrences all number
    112
    486
    32
    28
    115

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jun 2015
    Amendment 1 was issued to align the requirements for the duration of contraception to be used by patients during the study with the approved European Summary of Product Characteristics. According to the Exclusion criteria of the study protocol, women of childbearing potential had to use effective methods of contraception during dosing of study treatment and for 16 weeks after stopping treatment, in line with phase III AIN457A program study protocols. Therefore, the advice to female patients to prevent pregnancy was amended to cover also the contraception length post treatment requirements of the European Summary of Product Characteristics (20 weeks). In addition, the approved European Summary of Product Characteristics specifies for the pre-filled secukinumab syringe a warning and precaution for use in case a latex sensitivity would be pertinent for a patient. The removable needle cap of the pre-filled syringe contains a derivative of natural rubber latex; at time of the amendment, no natural rubber latex had been detected in the removable needle cap. Nevertheless, the use of pre-filled syringes in latex sensitive individuals had not been studied and therefore a potential risk of hypersensitivity reactions was seen which could not be completely ruled out. The Exclusion criteria of the study protocol had been updated accordingly, as well as the risks and benefits.

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

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