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    Clinical Trial Results:
    A multicenter, double-blind, randomized withdrawal extension study of subcutaneous secukinumab in prefilled syringes to demonstrate long-term efficacy, safety and tolerability up to 4 years in patients with moderate to severe chronic plaque-type psoriasis completing preceding psoriasis phase III studies with secukinumab

    Summary
    EudraCT number
    		 2012-000533-39
    Trial protocol
    		 IS   LV   SE   LT   ES   BE   EE   GB   DE   FI   HU   IT   PL  
    Global end of trial date
    26 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2018
    First version publication date
    11 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAIN457A2302E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01544595
    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
    26 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate the efficacy of secukinumab 150 mg or 300 mg in patients with moderate to severe chronic plaque-type psoriasis, who were PASI 75 responders at Week 52 of the core study, with respect to loss of PASI 75 up to Week 68 compared to placebo.
    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
    19 Jun 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 46
    Country: Number of subjects enrolled
    Australia: 32
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Canada: 73
    Country: Number of subjects enrolled
    Colombia: 21
    Country: Number of subjects enrolled
    Estonia: 52
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 44
    Country: Number of subjects enrolled
    Germany: 176
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    Guatemala: 55
    Country: Number of subjects enrolled
    Hungary: 27
    Country: Number of subjects enrolled
    Iceland: 55
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 70
    Country: Number of subjects enrolled
    Korea, Republic of: 36
    Country: Number of subjects enrolled
    Latvia: 36
    Country: Number of subjects enrolled
    Lithuania: 23
    Country: Number of subjects enrolled
    Poland: 64
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Taiwan: 43
    Country: Number of subjects enrolled
    United States: 215
    Worldwide total number of subjects
    1146
    EEA total number of subjects
    538
    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)
    1055
    From 65 to 84 years
    91
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Among the 1146 patients who completed the screening phase, 995 “PASI 75 responder at week 52” patients were randomized in a double blind fashion to either active treatment or placebo & entered the randomized withdrawal period and 151 “partial responders at week 52" patients entered treatment period of the Extension.

    Pre-assignment
    Screening details
    		 1366 patients who completed the core studies (CAIN457A2302 or CAIN457A2303) and provided consent for participation in the extension study were screened, and 1146 (83.9%) completed the screening phase and entered the extension.

    Period 1
    Period 1 title
    Status at Week 68
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    Randomised-Controlled

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 AIN457 150 mg –Randomized withdrawal period
    Arm description
    		 PASI 75 responders at Week 52, treated with AIN 150 mg in core study and randomized to AIN150 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    AIN457
    Investigational medicinal product code
    Other name
    Secukinumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration. The 150 mg/1 mL solution in PFS was used for s.c. 150 mg dose (1 syringe)

    Arm title
    		 AIN457 300 mg –Randomized withdrawal period
    Arm description
    		 PASI 75 responders at Week 52, treated with AIN 300 mg in core study and randomized to AIN300 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    AIN457
    Investigational medicinal product code
    Other name
    Secukinumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration. The 150 mg/1 mL solution in PFS was used for s.c. 300 mg dose (2 syringes)

    Arm title
    		 AIN457 150 mg Placebo - Randomized withdrawal period
    Arm description
    		 PASI 75 responders at Week 52, treated with AIN 150 mg in core study and randomized to placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    AIN457
    Investigational medicinal product code
    Other name
    Secukinumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration during the core study and randomized to placebo at week 52. Placebo secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration.

    Arm title
    		 AIN457 300 mg Placebo - Randomized withdrawal period
    Arm description
    		 PASI 75 responders at Week 52, treated with AIN 300 mg in core study and randomized to placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    AIN457
    Investigational medicinal product code
    Other name
    Secukinumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration (The 150 mg/1 mL solution in PFS was used for s.c. 300 mg dose (2 syringes)) during the core study and randomized to placebo at week 52. Placebo secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration.

    Number of subjects in period 1
    		AIN457 150 mg –Randomized withdrawal period AIN457 300 mg –Randomized withdrawal period AIN457 150 mg Placebo - Randomized withdrawal period AIN457 300 mg Placebo - Randomized withdrawal period
    Started
    301
    363
    150
    181
    Completed
    262
    346
    87
    130
    Not completed
    39
    17
    63
    51
         Consent withdrawn by subject
    -
    1
    1
    2
         Adverse event, non-fatal
    3
    2
    1
    -
         Technical problems
    1
    -
    -
    1
         Non-compliance with study treatment
    1
    -
    -
    1
         Moved to treatment period ≤ wk 68
    30
    13
    60
    46
         Lost to follow-up
    1
    1
    -
    -
         Lack of efficacy
    1
    -
    -
    -
         Protocol deviation
    2
    -
    1
    1
    Period 2
    Period 2 title
    Status at Week 156
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AIN457 150 mg –Randomized withdrawal period
    Arm description
    		 PASI 75 responders at Week 52, treated with AIN 150 mg in core study and randomized to AIN150 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    AIN457
    Investigational medicinal product code
    Other name
    Secukinumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration. The 150 mg/1 mL solution in PFS was used for s.c. 150 mg dose (1 syringe)

    Arm title
    		 AIN457 300 mg –Randomized withdrawal period
    Arm description
    		 PASI 75 responders at Week 52, treated with AIN 300 mg in core study and randomized to AIN300 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    AIN457
    Investigational medicinal product code
    Other name
    Secukinumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration. The 150 mg/1 mL solution in PFS was used for s.c. 300 mg dose (2 syringes)

    Arm title
    		 AIN457 150 mg Placebo - Randomized withdrawal period
    Arm description
    		 PASI 75 responders at Week 52, treated with AIN 150 mg in core study and randomized to placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    AIN457
    Investigational medicinal product code
    Other name
    Secukinumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration during the core study and randomized to placebo at week 52. Placebo secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration.

    Arm title
    		 AIN457 300 mg Placebo - Randomized withdrawal period
    Arm description
    		 PASI 75 responders at Week 52, treated with AIN 300 mg in core study and randomized to placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    AIN457
    Investigational medicinal product code
    Other name
    Secukinumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration (The 150 mg/1 mL solution in PFS was used for s.c. 300 mg dose (2 syringes)) during the core study and randomized to placebo at week 52. Placebo secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration.

    Arm title
    		 AIN457 150 mg - Partial responders
    Arm description
    		 PASI 50 responders / PASI 75 non responders at Week 52, treated with AIN 150 mg in core and extension study
    Arm type
    		 Experimental

    Investigational medicinal product name
    AIN457
    Investigational medicinal product code
    Other name
    Secukinumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration. The 150 mg/1 mL solution in PFS was used for s.c. 150 mg dose (1 syringe)

    Arm title
    		 AIN457 300 mg - Partial responders
    Arm description
    		 PASI 50 responders / PASI 75 non responders at Week 52, treated with AIN 300 mg in core and extension study
    Arm type
    		 Active comparator

    Investigational medicinal product name
    AIN457
    Investigational medicinal product code
    Other name
    Secukinumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 150 mg/1 mL solution for injection was provided in PFS for s.c. administration. The 150 mg/1 mL solution in PFS was used for s.c. 300 mg dose (2 syringes)

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Partial responder patients were not in 2 arms in period 1 (Week 68). These patients were part of another arm at this time.
    Number of subjects in period 2
    		AIN457 150 mg –Randomized withdrawal period AIN457 300 mg –Randomized withdrawal period AIN457 150 mg Placebo - Randomized withdrawal period AIN457 300 mg Placebo - Randomized withdrawal period AIN457 150 mg - Partial responders AIN457 300 mg - Partial responders
    Started
    301
    363
    150
    181
    98
    53
    Completed
    184
    285
    10
    15
    60
    38
    Not completed
    117
    78
    140
    166
    38
    15
         Consent withdrawn by subject
    9
    10
    4
    9
    20
    6
         Physician decision
    -
    3
    1
    -
    -
    -
         Adverse event, non-fatal
    9
    11
    1
    3
    4
    2
         Technical problems
    3
    1
    -
    1
    -
    -
         Moved to treatment period ≤ wk 156
    86
    44
    131
    145
    -
    -
         Non-compliance with study treatement
    -
    1
    -
    1
    -
    1
         Pregnancy
    2
    3
    -
    -
    -
    -
         Lost to follow-up
    4
    4
    -
    1
    4
    1
         Protocol deviation
    3
    1
    2
    2
    -
    -
         Lack of efficacy
    1
    -
    1
    4
    10
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AIN457 150 mg –Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 150 mg in core study and randomized to AIN150 mg

    Reporting group title
    AIN457 300 mg –Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 300 mg in core study and randomized to AIN300 mg

    Reporting group title
    AIN457 150 mg Placebo - Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 150 mg in core study and randomized to placebo

    Reporting group title
    AIN457 300 mg Placebo - Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 300 mg in core study and randomized to placebo

    Reporting group title
    AIN457 150 mg - Partial responders
    Reporting group description
    		 PASI 50 responders / PASI 75 non responders at Week 52, treated with AIN 150 mg in core and extension study

    Reporting group title
    AIN457 300 mg - Partial responders
    Reporting group description
    		 PASI 50 responders / PASI 75 non responders at Week 52, treated with AIN 300 mg in core and extension study

    Reporting group values
    		 AIN457 150 mg –Randomized withdrawal period AIN457 300 mg –Randomized withdrawal period AIN457 150 mg Placebo - Randomized withdrawal period AIN457 300 mg Placebo - Randomized withdrawal period AIN457 150 mg - Partial responders AIN457 300 mg - Partial responders Total
    Number of subjects
    		 301 363 150 181 98 53
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.9 ( 12.93 ) 45.8 ( 12.92 ) 47.1 ( 13.34 ) 45.4 ( 13.09 ) 46.8 ( 12.78 ) 48.5 ( 11.98 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 83 102 45 62 28 10 330
        Male
    		 218 261 105 119 70 43 816
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 213 276 115 136 73 42 855
        Black
    		 4 4 2 3 4 1 18
        Asian
    		 52 50 22 24 17 8 173
        Native American
    		 24 23 9 15 2 2 75
        Pacific Islander
    		 1 2 0 1 1 0 5
        Unknown
    		 0 1 1 1 0 0 3
        Other
    		 7 7 1 1 1 0 17

    End points

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    End points reporting groups
    Reporting group title
    AIN457 150 mg –Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 150 mg in core study and randomized to AIN150 mg

    Reporting group title
    AIN457 300 mg –Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 300 mg in core study and randomized to AIN300 mg

    Reporting group title
    AIN457 150 mg Placebo - Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 150 mg in core study and randomized to placebo

    Reporting group title
    AIN457 300 mg Placebo - Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 300 mg in core study and randomized to placebo
    Reporting group title
    AIN457 150 mg –Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 150 mg in core study and randomized to AIN150 mg

    Reporting group title
    AIN457 300 mg –Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 300 mg in core study and randomized to AIN300 mg

    Reporting group title
    AIN457 150 mg Placebo - Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 150 mg in core study and randomized to placebo

    Reporting group title
    AIN457 300 mg Placebo - Randomized withdrawal period
    Reporting group description
    		 PASI 75 responders at Week 52, treated with AIN 300 mg in core study and randomized to placebo

    Reporting group title
    AIN457 150 mg - Partial responders
    Reporting group description
    		 PASI 50 responders / PASI 75 non responders at Week 52, treated with AIN 150 mg in core and extension study

    Reporting group title
    AIN457 300 mg - Partial responders
    Reporting group description
    		 PASI 50 responders / PASI 75 non responders at Week 52, treated with AIN 300 mg in core and extension study

    Subject analysis set title
    AIN457 150 mg only
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients staying strictly on AIN457 150mg from Week 52

    Subject analysis set title
    AIN457 300 mg only
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients staying strictly on AIN457 300mg from Week 52

    Subject analysis set title
    Placebo - AIN457 150 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients randomized to placebo at Week 52, treated with AIN457 150mg after they relapsed

    Subject analysis set title
    Placebo - AIN457 300 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients randomized to placebo at Week 52, treated with AIN457 300mg after they relapsed

    Subject analysis set title
    Any AIN457 150 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety data from patients while on AIN457 150 mg

    Subject analysis set title
    Any AIN457 300 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety data from patients while on AIN457 300 mg

    Subject analysis set title
    Any AIN457
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    safety data from patients while on any dose of AIN457

    Primary: Subjects with Loss of Psoriasis Area and Severity Index (PASI) 75 response up to Week 68

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    End point title
    		 Subjects with Loss of Psoriasis Area and Severity Index (PASI) 75 response up to Week 68
    End point description
    The primary variable was the cumulative rate of patients who lost PASI 75 response up to Week 68 (time=0 being defined as Week 52). Loss of PASI 75 response was analyzed by means of a survival analysis defining “loss of PASI 75 response” as “failure”. The term cumulative rate corresponded to 1 minus the survival function within this survival analysis, and the cumulative rate and the survival functions were dependent on time t. PASI 75 response: patients achieving ≥ 75% improvement (reduction) in PASI score compared to baseline of the core study were defined as PASI 75 responders.
    End point type
    Primary
    End point timeframe
    At week 68 (16 weeks after week 52)
    End point values
    		 AIN457 150 mg –Randomized withdrawal period AIN457 300 mg –Randomized withdrawal period AIN457 150 mg Placebo - Randomized withdrawal period AIN457 300 mg Placebo - Randomized withdrawal period
    Number of subjects analysed
    297
    363
    150
    180
    Units: cumulative rate
        number (confidence interval 95%)
    49.8 (25.8 to 79.7)
    25.4 (9.8 to 56.5)
    74.3 (56.9 to 88.8)
    64.7 (52.0 to 77.2)
    Statistical analysis title
    		 Cumulative rate of PASI response
    Statistical analysis description
    The following hypotheses were tested for 52 weeks≤ t ≤68 weeks • H1: p1(t) – p0,1(t) = 0 versus HA1: p1(t)– p0,1(t) ≥ 0, • H2: p2(t) – p0,2(t) = 0 versus HA2: p2(t) – p0,2(t) ≥ 0,
    Comparison groups
    AIN457 150 mg –Randomized withdrawal period v AIN457 150 mg Placebo - Randomized withdrawal period
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.42
    Notes
    [1] - H1: Secukinumab 150 mg was not different from placebo with respect to the cumulative rate for patients who lost PASI 75 response up to Week 68 • H2: Secukinumab 300 mg was not different from placebo with respect to the cumulative rate for patients who lost PASI 75 response up to Week 68
    Statistical analysis title
    		 Cumulative rate of PASI response
    Statistical analysis description
    The following hypotheses were tested for 52 weeks≤ t ≤68 weeks • H1: p1(t) – p0,1(t) = 0 versus HA1: p1(t)– p0,1(t) ≥ 0, • H2: p2(t) – p0,2(t) = 0 versus HA2: p2(t) – p0,2(t) ≥ 0,
    Comparison groups
    AIN457 300 mg –Randomized withdrawal period v AIN457 300 mg Placebo - Randomized withdrawal period
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.29
    Notes
    [2] - H1: Secukinumab 150 mg was not different from placebo with respect to the cumulative rate for patients who lost PASI 75 response up to Week 68 • H2: Secukinumab 300 mg was not different from placebo with respect to the cumulative rate for patients who lost PASI 75 response up to Week 68

    Secondary: Number of participants with PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 (observed data) - randomized withdrawal period

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    End point title
    		 Number of participants with PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 (observed data) - randomized withdrawal period
    End point description
    Psoriasis Area and Severity Index (PASI) 75 responder at week 52. Patients in the placebo groups were not evaluable after re-treatment with Secukinumab. PASI 75 Responders: patients with a PASI 75 response (patients achieving ≥75% improvement [reduction] in PASI score compared to baseline of the core study). PASI 50 response: patients achieving ≥ 50% improvement (reduction) in PASI score compared to baseline of the core study were defined as PASI 50 responders. PASI 90 response: patients achieving ≥ 90% improvement (reduction) in PASI score compared to baseline of the core study were defined as PASI 90 responders. PASI 100 response/remission: complete clearing of psoriasis (PASI=0)
    End point type
    Secondary
    End point timeframe
    Week 52, 104, and 156
    End point values
    		 AIN457 150 mg –Randomized withdrawal period AIN457 300 mg –Randomized withdrawal period AIN457 150 mg Placebo - Randomized withdrawal period AIN457 300 mg Placebo - Randomized withdrawal period
    Number of subjects analysed
    297
    363
    150
    180
    Units: Number of participants
        Wk 52 - IGA 0/1|
    208
    309
    112
    157
        Wk 52 - PASI 50|
    297
    363
    149
    180
        Wk 52 - PASI 75|
    296
    361
    149
    179
        Wk 52 - PASI 90|
    190
    303
    105
    156
        Wk 52 - PASI 100|
    93
    191
    54
    96
        Wk 104 - IGA 0/1 (n=260, 338, 20, 34)|
    128
    236
    8
    13
        Wk 104 - PASI 50 (n=260, 338, 20,34)|
    254
    329
    19
    28
        Wk 104 - PASI 75 (n=260, 338, 20,34)|
    209
    299
    15
    21
        Wk 104 - PASI 90 (n=260, 338, 20,34)|
    125
    240
    6
    13
        Wk 104 - PASI 100 (n=260, 338, 20,34)|
    65
    151
    4
    6
        Wk 156 - IGA 0/1 (n=239, 324, 10,15)|
    90
    202
    4
    7
        Wk 156 - PASI 50 (n=239, 324, 10,15)|
    230
    322
    10
    15
        Wk 156 - PASI 75 (n=239, 324, 10,15)|
    183
    287
    6
    13
        Wk 156 - PASI 90 (n=239, 324, 10,15)|
    101
    207
    4
    7
        Wk 156 - PASI 100 (n=239, 324, 10,15)|
    47
    117
    2
    5
    No statistical analyses for this end point

    Secondary: Number of participant with PASI 50, PASI 75, PASI 90, and PASI 100 (observed data) - entire study period

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    End point title
    		 Number of participant with PASI 50, PASI 75, PASI 90, and PASI 100 (observed data) - entire study period
    End point description
    Psoriasis Area and Severity Index (PASI) scoring system: The average degree of severity of each sign in each of the four body regions was assigned a score of 0-4. The area covered by lesions on each body region was estimated as a percentage of the total area of that particular body region.
    End point type
    Secondary
    End point timeframe
    Week 52, Week 104, Week 156, week 208, week 260
    End point values
    		 AIN457 150 mg only AIN457 300 mg only
    Number of subjects analysed
    164
    416
    Units: Number of participants
        Wk 52 - PASI 50|
    164
    416
        Wk 52 - PASI 75|
    121
    361
        Wk 52 - PASI 90|
    85
    303
        Wk 52 - PASI 100|
    54
    191
        Wk 104 - PASI 50 (n=104, 377)|
    99
    359
        Wk 104 - PASI 75 (n=104, 377)|
    76
    314
        Wk 104 - PASI 90 (n=104, 377)|
    62
    243
        Wk 104 - PASI 100 (n=104, 377)|
    46
    153
        Wk 156 - PASI 50 (n=69, 361)|
    67
    351
        Wk 156 - PASI (n=69, 361)|
    63
    297
        Wk 156 - PASI 90 (n=69, 361)|
    52
    211
        Wk 156 - PASI 100 (n=69, 361)|
    37
    118
        Wk 208 - PASI 50 (n=58, 323)|
    58
    316
        Wk 208 - PASI 75 (n=58, 323)|
    55
    269
        Wk 208 - PASI 90 (n=58, 323)|
    51
    194
        Wk 208 - PASI 100 (n=58, 323)|
    33
    104
        Wk 260 - PASI 50 (n=51, 285)|
    51
    279
        Wk 260 - PASI 75 (n=51, 285)|
    49
    231
        Wk 260 - PASI 90 (n=51, 285)|
    37
    179
        Wk 260 - PASI 100 (n=51, 285)|
    26
    100
    No statistical analyses for this end point

    Secondary: Percent change from baseline for PASI score over time (observed data) - Randomized withdrawal period

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    End point title
    		 Percent change from baseline for PASI score over time (observed data) - Randomized withdrawal period
    End point description
    The improvement (decrease from baseline) in PASI total scores observed at Week 52. Perc. change = 100 x Abs. change /Base. (Abs. change = Post - Base) For each post-baseline visit only patients with a value at both baseline and the respective post-baseline visit are included.
    End point type
    Secondary
    End point timeframe
    Week 52, 104, and 156
    End point values
    		 AIN457 150 mg –Randomized withdrawal period AIN457 300 mg –Randomized withdrawal period AIN457 150 mg Placebo - Randomized withdrawal period AIN457 300 mg Placebo - Randomized withdrawal period
    Number of subjects analysed
    297
    363
    150
    180
    Units: Percent change in PASI score
    arithmetic mean (standard deviation)
        Week 52 (baseline)|
    -92.31 ( 7.878 )
    -95.98 ( 6.638 )
    -92.88 ( 8.435 )
    -96.16 ( 6.030 )
        Week 104 (n=260, 338, 20, 34)|
    -85.88 ( 14.631 )
    -91.51 ( 13.221 )
    -82.67 ( 15.568 )
    -78.04 ( 20.986 )
        Week 156 (n=239, 324, 10, 15)|
    -83.32 ( 17.341 )
    -90.50 ( 11.660 )
    -79.77 ( 15.172 )
    -86.35 ( 15.602 )
    No statistical analyses for this end point

    Secondary: Percent change from baseline for PASI score over time (observed data) - entire study period

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    End point title
    		 Percent change from baseline for PASI score over time (observed data) - entire study period
    End point description
    Perc. change = 100 x Abs. change /Base. (Abs. change = Post - Base) For each post-baseline visit only patients with a value at both baseline and the respective post-baseline visit are included.
    End point type
    Secondary
    End point timeframe
    Week 52, Week 104, Week 156, week 208, week 260
    End point values
    		 AIN457 150 mg only AIN457 300 mg only
    Number of subjects analysed
    164
    416
    Units: Percent change in PASI score
    arithmetic mean (standard deviation)
        Wk 52|
    -85.93 ( 14.815 )
    -91.82 ( 11.889 )
        Wk 104 (n=104, 377)|
    -85.97 ( 18.811 )
    -88.86 ( 16.151 )
        Wk 156 (n=69, 361)|
    -93.03 ( 12.338 )
    -87.78 ( 15.114 )
        Wk 208 (n=58, 323)|
    -95.71 ( 7.868 )
    -88.25 ( 14.496 )
        Wk 260 (n=51, 285)|
    -93.65 ( 9.959 )
    -88.08 ( 14.983 )
    No statistical analyses for this end point

    Secondary: Number of participants in each IGA mod 2011 category (observed data)- randomized withdrawal period

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    End point title
    		 Number of participants in each IGA mod 2011 category (observed data)- randomized withdrawal period
    End point description
    Investigator Global Assessment (IGA) mod 2011; scale from 0 - 4. Score 0: Clear (No signs of psoriasis. Post-inflammatory hyperpigmentation could be Present). Score 1: Almost clear (Normal to pink coloration of lesions; no thickening; no to minimal focal scaling), Score 2: Mild (Pink to light red coloration; just detectable to mild thickening; predominantly fine scaling). Score 3: Moderate (Dull bright red, clearly distinguishable erythema; clearly distinguishable to moderate thickening; moderate scaling). Score 4: Severe (Bright to deep dark red coloration; severe thickening with hard edges; severe /coarse scaling covering almost all or all lesions). Patients in the placebo groups were not evaluable after re-treatment with Secukinumab
    End point type
    Secondary
    End point timeframe
    Week 52 (baseline), 104, and 156
    End point values
    		 AIN457 150 mg –Randomized withdrawal period AIN457 300 mg –Randomized withdrawal period AIN457 150 mg Placebo - Randomized withdrawal period AIN457 300 mg Placebo - Randomized withdrawal period
    Number of subjects analysed
    297
    363
    150
    180
    Units: Number of participants
        Wk 52 - clear|
    95
    188
    56
    94
        Wk 52 - almost clear|
    113
    121
    56
    63
        Wk 52 - mild|
    75
    44
    33
    22
        Wk 52 - moderate|
    14
    9
    4
    1
        Wk 52 - severe|
    0
    1
    1
    0
        Wk 104 - clear (n=260, 338, 20, 34)|
    66
    152
    3
    4
        Wk 104 - almost clear (n=260, 338, 20, 34)|
    62
    84
    5
    9
        Wk 104 - mild v(n=260, 338, 20, 34)|
    78
    64
    9
    9
        Wk 104 - moderate (n=260, 338, 20, 34)|
    47
    33
    3
    10
        Wk 104 - severe (n=260, 338, 20, 34)|
    7
    5
    0
    2
        Wk 156 - clear (n=239, 324, 10, 15)|
    48
    115
    2
    4
        Wk 156 - almost clear (n=239, 324, 10, 15)|
    42
    87
    2
    3
        Wk 156 - mild (n=239, 324, 10, 15)|
    88
    78
    2
    5
        Wk 156 - moderate (n=239, 324, 10, 15)|
    59
    43
    4
    2
        Wk 156 - severe (n=239, 324, 10, 15)|
    2
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Number of participants in each IGA mod 2011 category (observed data) - entire study period

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    End point title
    		 Number of participants in each IGA mod 2011 category (observed data) - entire study period
    End point description
    Investigator’s Global Assessment (IGA) mod 2011; scale from 0 - 4. Score 0= clear (no signs of psoriasis) Score 1 = almost clear no to minimal local scaling) Score 2 = mild (predominantly fine scaling) Score 3 = moderate (moderate scaling) Score 4 = severe (severe/coarse scaling covering almost all or all lesions)
    End point type
    Secondary
    End point timeframe
    Week 52, Week 104, Week 156, week 208, week 260
    End point values
    		 AIN457 150 mg only AIN457 300 mg only
    Number of subjects analysed
    164
    416
    Units: Number of participants
        Wk 52 - clear|
    56
    188
        Wk 52 - almost clear|
    38
    123
        Wk 52 - mild|
    44
    71
        Wk 52 - moderate|
    26
    32
        Wk 52 - severe|
    0
    2
        Wk 104 - clear (n=104, 377)|
    47
    154
        Wk 104 - almost clear (n=104, 377)|
    16
    85
        Wk 104 - mild (n=104, 377)|
    17
    80
        Wk 104 - moderate (n=104, 377)|
    19
    51
        Wk 104 - severe (n=104, 377)|
    5
    7
        Wk 156 - clear (n=104, 377)|
    37
    116
        Wk 156 - almost clear (n=69, 361)|
    13
    90
        Wk 156 - mild (n=69, 361)|
    11
    91
        Wk 156 - moderate (n=69, 361)|
    8
    61
        Wk 156 - severe (n=69, 361)|
    0
    3
        Wk 208 - clear (n=58, 323)|
    33
    102
        Wk 208 - almost clear (n=58, 323)|
    14
    81
        Wk 208 - mild (n=58, 323)|
    7
    88
        Wk 208 - moderate (n=58, 323)|
    3
    47
        Wk 208 - severe (n=58, 323)|
    1
    5
        Wk 260 - clear (n=51, 285)|
    27
    97
        Wk 260 - almost clear (n=51, 285)|
    12
    65
        Wk 260 - mild (n=51, 285)|
    8
    66
        Wk 260 - moderate (n=51, 285)|
    4
    53
        Wk 260 - severe (n=51, 285)|
    0
    4
    No statistical analyses for this end point

    Secondary: Number of participants with IGA mod 2011 0/1 response (observed data) - entire study period

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    End point title
    		 Number of participants with IGA mod 2011 0/1 response (observed data) - entire study period
    End point description
    Investigator’s Global Assessment (IGA) mod 2011 0/1. Score 0= clear (no signs of psoriasis) Score 1 = almost clear no to minimal local scaling) Score 2 = mild (predominantly fine scaling) Score 3 = moderate (moderate scaling) Score 4 = severe (severe/coarse scaling covering almost all or all lesions) Based on this scale, a patient was considered as IGA mod 2011 0/1 responder if the patient achieved a score of 0 or 1 and improved by at least 2 points on the IGA scale compared to baseline.
    End point type
    Secondary
    End point timeframe
    Week 52, Week 104, Week 156, week 208, week 260
    End point values
    		 AIN457 150 mg only AIN457 300 mg only
    Number of subjects analysed
    164
    416
    Units: Number of participants
        Wk 52|
    94
    311
        Wk 104 (n=104, 377)|
    63
    239
        Wk 156 (n=69, 361)|
    50
    206
        Wk 208 (n=58, 323)|
    47
    183
        Wk 260 (n=51, 285)|
    39
    162
    No statistical analyses for this end point

    Secondary: Loss of IGA mod 2011 0 or 1 response over time for subjects with IGA mod 2011 0 or 1 response at Week 52 - randomized withdrawal period

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    End point title
    		 Loss of IGA mod 2011 0 or 1 response over time for subjects with IGA mod 2011 0 or 1 response at Week 52 - randomized withdrawal period
    End point description
    Summary for loss of IGA mod 2011 0 or 1 response over time for patients with response at Week 52. time = 0 refers to Week 52
    End point type
    Secondary
    End point timeframe
    Week 68
    End point values
    		 AIN457 150 mg –Randomized withdrawal period AIN457 300 mg –Randomized withdrawal period AIN457 150 mg Placebo - Randomized withdrawal period AIN457 300 mg Placebo - Randomized withdrawal period
    Number of subjects analysed
    297
    363
    150
    180
    Units: Loss of IGA mod 2011 0 or 1 response
        number (confidence interval 95%)
    38.1 (29.8 to 47.7)
    33.4 (25.7 to 42.6)
    82.1 (71.2 to 90.8)
    65.5 (53.8 to 77.0)
    No statistical analyses for this end point

    Secondary: Time to PASI 75 response - treatment period for re-treated after relapse

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    End point title
    		 Time to PASI 75 response - treatment period for re-treated after relapse
    End point description
    PASI 75 response since reinitiating treatment after relapse. time = 0 refers to Week 52
    End point type
    Secondary
    End point timeframe
    up to week 260
    End point values
    		 Placebo - AIN457 150 mg Placebo - AIN457 300 mg
    Number of subjects analysed
    131
    145
    Units: PASI 75 response
    number (confidence interval 95%)
        0 to <=4 wks|
    38.5 (30.7 to 47.4)
    51.0 (43.2 to 59.5)
        >12 to <=16 wks (n=21,13)|
    91.2 (85.5 to 95.3)
    95.1 (90.7 to 97.8)
        >80 to <=84 wks (n=2,1)|
    96.8 (92.6 to 98.9)
    98.8 (94.8 to 99.9)
    No statistical analyses for this end point

    Secondary: Time to IGA mod 0 or 1 response - treatment period for re-treated after relapse

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    End point title
    		 Time to IGA mod 0 or 1 response - treatment period for re-treated after relapse
    End point description
    IGA mod 2011 0 or 1 response since reinitiating treatment after relapse for subjects with IGA 0 or 1 response at week 52 and not have IGA 0 or 1 response at relapse. time = 0 refers to Week 52
    End point type
    Secondary
    End point timeframe
    up to week 260
    End point values
    		 Placebo - AIN457 150 mg Placebo - AIN457 300 mg
    Number of subjects analysed
    131
    145
    Units: IGA 0 or 1 response
    number (confidence interval 95%)
        0 to <=4 wks (n=96,123)|
    12.5 (7.3 to 21.0)
    28.1 (21.0 to 37.0)
        >12 to <=16 wks (n=40,32)|
    75.0 (66.0 to 83.1)
    83.5 (76.3 to 89.4)
        >84 to <=88 wks (n=7,4)|
    87.9 (80.0 to 93.8)
    90.8 (84.5 to 95.4)
    No statistical analyses for this end point

    Secondary: Relapse over time - randomized withdrawal period

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    End point title
    		 Relapse over time - randomized withdrawal period
    End point description
    Time 0 = week 52
    End point type
    Secondary
    End point timeframe
    up to week 156
    End point values
    		 AIN457 150 mg –Randomized withdrawal period AIN457 300 mg –Randomized withdrawal period AIN457 150 mg Placebo - Randomized withdrawal period AIN457 300 mg Placebo - Randomized withdrawal period
    Number of subjects analysed
    297
    363
    150
    180
    Units: Relapse
    number (confidence interval 95%)
        0 to <=4 wks (n=286,353,150,180)|
    0.3 (0.0 to 2.4)
    0.3 (0.0 to 1.9)
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.0)
        >12 to <=16 wks (n=297,363,124,160)|
    3.1 (1.6 to 5.9)
    2.2 (1.1 to 4.4)
    19.8 (13.9 to 27.7)
    12.1 (8.0 to 18.1)
        >92 to <=96 wks (n=188,292,11,15)|
    21.5 (16.9 to 27.0)
    9.4 (6.8 to 13.1)
    88.1 (80.9 to 93.5)
    86.1 (79.6 to 91.4)
        >104 to <=108 wks (n=156,297,8,9)|
    21.9 (17.3 to 27.5)
    9.4 (6.8 to 13.1)
    88.1 (80.9 to 93.5)
    86.1 (79.6 to 91.4)
    No statistical analyses for this end point

    Secondary: Percentage of participants experiencing relapse after last injection

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    End point title
    		 Percentage of participants experiencing relapse after last injection
    End point description
    Relapse: when the achieved maximal PASI improvement from baseline of core study was reduced by >50%. Time 0 = week 52
    End point type
    Secondary
    End point timeframe
    up to week 16
    End point values
    		 AIN457 150 mg only AIN457 300 mg only
    Number of subjects analysed
    164
    416
    Units: relapses
    number (confidence interval 95%)
        0 to <=4 wks (n=158,415)|
    7.2 (4.0 to 12.6)
    2.0 (1.0 to 3.9)
        >12 to <=16 wks (n=66,208)|
    34.0 (22.6 to 48.9)
    28.4 (21.8 to 36.6)
    No statistical analyses for this end point

    Secondary: Percentage of participants experiencing rebound after last injection

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    End point title
    		 Percentage of participants experiencing rebound after last injection
    End point description
    Rebound: PASI increases to > 125% of baseline (where baseline is the PASI at the randomization of the core study) or presence of new pustular psoriasis, new erythrodermic psoriasis or more inflammatory psoriasis occurring within 8 Weeks of stopping therapy (after the last dose of study treatment received). Rebound like event (RLE) was defined as increase of PASI of > 125% from baseline value or occurrence of new pustular, new erythrodermic or more inflammatory psoriasis any time after stopping therapy (last treatment administered) up to Week 68. Rebound was evaluated for the patients randomized to the placebo groups in the extension study; hence these patients received the last dose of secukinumab during the core studies.
    End point type
    Secondary
    End point timeframe
    up to week 68
    End point values
    		 AIN457 150 mg only AIN457 300 mg only
    Number of subjects analysed
    164
    416
    Units: Percentage of participants
    number (confidence interval 95%)
        Rebound (<8 wks after last inj.; n=108,320)|
    8.3 (4.1 to 15.6)
    6.6 (4.2 to 10.0)
        RLE (< 12 wks after last inj., n=110,326)|
    11.8 (6.7 to 19.7)
    9.5 (6.7 to 13.4)
    No statistical analyses for this end point

    Secondary: Number of patients with Dermatology Life Quality Index response (DLQI 0 or 1) - randomized withdrawal period (observed data)

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    End point title
    		 Number of patients with Dermatology Life Quality Index response (DLQI 0 or 1) - randomized withdrawal period (observed data)
    End point description
    Dermatology Life Quality Index (DLQI) scores range from 0 to 30. Lower absolute scores on DLQI indicate better/improved health-related quality-of life impairment.
    End point type
    Secondary
    End point timeframe
    Week 52 (baseline), 64, 76, 88, 104, 116, 128, 140, and 156
    End point values
    		 AIN457 150 mg –Randomized withdrawal period AIN457 300 mg –Randomized withdrawal period AIN457 150 mg Placebo - Randomized withdrawal period AIN457 300 mg Placebo - Randomized withdrawal period
    Number of subjects analysed
    295
    359
    150
    180
    Units: Number of participants
        Week 52 (baseline)|
    196
    281
    109
    142
        Week 64 (n=290,357,126,162)|
    170
    265
    59
    90
        Week 76 (n=284,352,71,104)|
    163
    256
    26
    38
        Week 88 (n=281,346,34,62)|
    157
    247
    18
    24
        Week 104 (n=262,337,21,35)|
    146
    237
    10
    14
        Week 116 (n=252,326,16,24)|
    141
    230
    6
    9
        Week 128 (n=251,326,14,19)|
    139
    222
    4
    10
        Week 140 (n=241,327,12,18)|
    126
    229
    4
    7
        Week 156 (n=240,324,11,15)|
    119
    215
    5
    8
    No statistical analyses for this end point

    Secondary: Number of subjects with Dermatology Life Quality Index response (DLQI 0 or 1) - entire treatment period

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    End point title
    		 Number of subjects with Dermatology Life Quality Index response (DLQI 0 or 1) - entire treatment period
    End point description
    Dermatology Life Quality Index (DLQI) scores range from 0 to 30. Lower absolute scores on DLQI indicate better/improved health-related quality-of life impairment.
    End point type
    Secondary
    End point timeframe
    Week 52 (baseline), 64, 76, 88, 104, 116, 128, 140, and 156
    End point values
    		 AIN457 150 mg only AIN457 300 mg only
    Number of subjects analysed
    164
    416
    Units: Number of participants
        Week 52 (baseline, n=162,95)|
    95
    299
        Week 104 (n=113, 377)|
    66
    254
        week 156 (n=69,362)|
    47
    225
        Week 208 (n=53,328)|
    41
    207
        week 260 (n=52,286)|
    42
    174
    No statistical analyses for this end point

    Secondary: EQ-5D health state assessment (observed value)

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    End point title
    		 EQ-5D health state assessment (observed value)
    End point description
    EQ-5D: EuroQOL 5-Dimension Health Status Questionnaire. The EQ-5D© is a generic instrument to assess each patient’s health status. It provides a simple descriptive profile and a single index value for health status. The EQ visual analog scale records the respondent’s self-rated health on a vertical scale where the endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable health state’. This information can be used as a quantitative measure of health outcome as judged by the individual respondents.
    End point type
    Secondary
    End point timeframe
    week 64, 76, 88, 104, 116, 128, 140, and 156
    End point values
    		 AIN457 150 mg only AIN457 300 mg only
    Number of subjects analysed
    164
    416
    Units: Percent change
    arithmetic mean (standard deviation)
        Week 64 (n=155,404)|
    -1.33 ( 22.506 )
    1.44 ( 26.815 )
        Week 76 (n=144,398)|
    -1.99 ( 22.339 )
    2.10 ( 28.493 )
        Week 88 (n=130,387)|
    -0.66 ( 24.558 )
    1.45 ( 28.269 )
        Week 104 (n=112,376)|
    -4.15 ( 27.823 )
    0.65 ( 23.454 )
        Week 116 (n=93,364)|
    -1.19 ( 21.022 )
    1.21 ( 23.681 )
        Week 128 (n=84,365)|
    -2.85 ( 23.584 )
    1.93 ( 27.840 )
        Week 140 (n=75,367)|
    0.09 ( 20.814 )
    -0.44 ( 18.504 )
        Week 156 (n=67,365)|
    2.13 ( 32.326 )
    1.19 ( 21.548 )
    No statistical analyses for this end point

    Secondary: Clinical laboratory evaluation: the number of participants with clinically CTCAE - entire study period

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    End point title
    		 Clinical laboratory evaluation: the number of participants with clinically CTCAE - entire study period
    End point description
    CTCAE: common terminology criteria for adverse events. A subject with multiple variable measurements is counted only once under the worst condition. LLN = lowever limit of normal.
    End point type
    Secondary
    End point timeframe
    approximately 4 years
    End point values
    		 Any AIN457 150 mg Any AIN457 300 mg Any AIN457
    Number of subjects analysed
    545
    890
    1113
    Units: 10E9/L
        Leukocytes (<LLN-3.0x10e9 /L, n=545,832,1037)|
    55
    59
    114
        Leukocytes (<3.0-2.0 x 10e9 /L, n=545,866,1080)|
    10
    7
    17
        Leukocytes (<2.0-1.0x10e9 /L, n=545,870,1085)|
    1
    0
    1
        Leukocytes (<1.0x10e9 /L, n=545,870,1085)|
    0
    0
    0
        Lymphocytes (<LLN-0.8x10e9 /L, n=545,840,1041)|
    47
    61
    108
        Lymphocytes (<0.8-0.5x10e9 /L, n=545,861,1071)|
    18
    28
    46
        Lymphocytes (<0.5-0.2 x 10e9 /L, n=545,864,1075)|
    1
    1
    2
        Lymphocytes (<0.2x10e9 /L, n=545,864,1075)|
    0
    0
    0
        Neutrophils (<LLN-1.5x10e9 /L, n=545,831,1037)|
    54
    69
    123
        Neutrophils (<1.5-1.0x10e9 /L, n=545,861,1071)|
    12
    20
    32
        Neutrophils (<1.0 - 0.5x10e9 /L, n=545,863,1074)|
    7
    4
    11
        Neutrophils (<0.5x10e9 /L, n=545,864,1075)|
    0
    0
    0
        Platelets (LLN-75x10e9 /L, n=545,836,1042)|
    24
    39
    63
        Platelets (<75-50x10e9 /L, n=545,862,1074)|
    2
    2
    4
        Platelets (<50-25 x 10e9 /L, n=545,862,1074)|
    0
    0
    0
        Platelets (<25x10e9 /L, n=545,862,1074)|
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Electrocardiogram: Number of participants with ECG test results - entire treatment period

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    End point title
    		 Electrocardiogram: Number of participants with ECG test results - entire treatment period
    End point description
    QTcB: QT interval corrected using Bazett’s formula QTcF: QT interval corrected using Fridericia’s formula A patient with multiple variable measurements is counted only once under the worst condition.
    End point type
    Secondary
    End point timeframe
    Approximately 4 years
    End point values
    		 Any AIN457 150 mg Any AIN457 300 mg Any AIN457
    Number of subjects analysed
    545
    890
    1113
    Units: Participants
        QTcB>500 msec (n=545,851,1060)|
    1
    2
    3
        QTcB>480 msec (n=545,848,1056)|
    8
    23
    30
        QTcB>450 msec (n=545,804,1004)|
    86
    159
    218
        QTcB changes from baseline>30 ms (n=545,851,1060)|
    124
    223
    316
        QTcB changes from baseline>60 ms (n=545,851,1060)|
    7
    19
    25
        QTcF>500 msec (n=545,851,1060)|
    0
    1
    1
        QTcF>480 msec (n=545,851,1059)|
    3
    6
    8
        QTcF>450 msec (n=545,838,1043)|
    35
    67
    93
        QTcF changes from baseline>30 ms (n=545,851,1060)|
    69
    127
    184
        QTcF changes from baseline>60 ms (n=545,851,1060)|
    1
    3
    4
        PR>250 msec (n=545,845,1051)|
    4
    5
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Any AIN457 150 mg
    Reporting group description
    		 Any AIN457 150 mg

    Reporting group title
    Any AIN457 300 mg
    Reporting group description
    		 Any AIN457 300 mg

    Reporting group title
    Any AIN457 dose
    Reporting group description
    		 Any AIN457 dose

    Reporting group title
    AIN457 300 mg (Core)- Placebo
    Reporting group description
    		 AIN457 300 mg (Core)- Placebo

    Reporting group title
    AIN457 150 mg (Core)- Placebo
    Reporting group description
    		 AIN457 150 mg (Core)- Placebo

    Serious adverse events
    		 Any AIN457 150 mg Any AIN457 300 mg Any AIN457 dose AIN457 300 mg (Core)- Placebo AIN457 150 mg (Core)- Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    61 / 545 (11.19%)
    143 / 890 (16.07%)
    198 / 1113 (17.79%)
    13 / 181 (7.18%)
    4 / 150 (2.67%)
         number of deaths (all causes)
    0
    2
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Anal squamous cell carcinoma
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Breast cancer
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder cancer
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Hepatic cancer metastatic
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningioma benign
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Metastases to lung
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 545 (0.37%)
    1 / 890 (0.11%)
    3 / 1113 (0.27%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Hypertension
         subjects affected / exposed
    1 / 545 (0.18%)
    1 / 890 (0.11%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 545 (0.00%)
    3 / 890 (0.34%)
    3 / 1113 (0.27%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Varicose vein
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous complete
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    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
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    1 / 181 (0.55%)
    0 / 150 (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
    Face oedema
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Medical device site granuloma
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    1 / 181 (0.55%)
    0 / 150 (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
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Ovarian cyst
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Vaginal cyst
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Asthma
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Laryngeal oedema
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Nasal septum deviation
         subjects affected / exposed
    1 / 545 (0.18%)
    2 / 890 (0.22%)
    3 / 1113 (0.27%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Sinus polyp
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Sleep apnoea syndrome
         subjects affected / exposed
    2 / 545 (0.37%)
    0 / 890 (0.00%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    1 / 545 (0.18%)
    1 / 890 (0.11%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aversion
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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 / 1
    0 / 1
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    3 / 545 (0.55%)
    2 / 890 (0.22%)
    5 / 1113 (0.45%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
    1 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Schizophrenia
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Substance abuse
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device loosening
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Ankle fracture
         subjects affected / exposed
    2 / 545 (0.37%)
    1 / 890 (0.11%)
    3 / 1113 (0.27%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac procedure complication
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Concussion
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Contusion
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Facial bones fracture
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    1 / 181 (0.55%)
    0 / 150 (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
    Fibula fracture
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 545 (0.00%)
    3 / 890 (0.34%)
    3 / 1113 (0.27%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    1 / 181 (0.55%)
    0 / 150 (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
    Humerus fracture
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Incisional hernia
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Jaw fracture
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney rupture
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Ligament injury
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    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
    1 / 545 (0.18%)
    2 / 890 (0.22%)
    3 / 1113 (0.27%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Lower limb fracture
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 545 (0.00%)
    3 / 890 (0.34%)
    3 / 1113 (0.27%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Procedural hypertension
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Radius fracture
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Spinal fracture
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Tendon injury
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Tendon rupture
         subjects affected / exposed
    0 / 545 (0.00%)
    3 / 890 (0.34%)
    3 / 1113 (0.27%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    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 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    0 / 181 (0.00%)
    1 / 150 (0.67%)
         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
    Ulna fracture
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Wrist fracture
         subjects affected / exposed
    1 / 545 (0.18%)
    2 / 890 (0.22%)
    3 / 1113 (0.27%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Malformation venous
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Acute myocardial infarction
         subjects affected / exposed
    0 / 545 (0.00%)
    4 / 890 (0.45%)
    4 / 1113 (0.36%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 545 (0.00%)
    4 / 890 (0.45%)
    4 / 1113 (0.36%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    1 / 545 (0.18%)
    9 / 890 (1.01%)
    10 / 1113 (0.90%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 9
    2 / 10
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Coronary artery disease
         subjects affected / exposed
    1 / 545 (0.18%)
    3 / 890 (0.34%)
    4 / 1113 (0.36%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    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
    0 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    0 / 181 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 545 (0.18%)
    2 / 890 (0.22%)
    3 / 1113 (0.27%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 3
    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 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Tachycardia paroxysmal
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Cerebral ischaemia
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complex regional pain syndrome
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Cranial nerve paralysis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Dizziness
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drooling
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Intracranial aneurysm
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Parkinson's disease
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Dyspepsia
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Enterocolitis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Functional gastrointestinal disorder
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Gastric ulcer
         subjects affected / exposed
    1 / 545 (0.18%)
    1 / 890 (0.11%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Haemorrhoids
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Ileus paralytic
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Intestinal polyp
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Intestinal pseudo-obstruction
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Large intestinal stenosis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 545 (0.18%)
    1 / 890 (0.11%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Umbilical hernia
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia, obstructive
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 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 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Cholangitis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Cholecystitis
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    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
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 545 (0.37%)
    1 / 890 (0.11%)
    3 / 1113 (0.27%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Hepatitis toxic
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Dermal cyst
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Dermatitis contact
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Diabetic foot
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Drug eruption
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    2 / 545 (0.37%)
    3 / 890 (0.34%)
    5 / 1113 (0.45%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
    1 / 5
    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 urinary
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Chronic kidney disease
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Nephrolithiasis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Nephrotic syndrome
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Pollakiuria
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Ureterolithiasis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Urethral stenosis
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperandrogenism
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid mass
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    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
    Arthralgia
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dupuytren's contracture
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint instability
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 545 (0.18%)
    2 / 890 (0.22%)
    3 / 1113 (0.27%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Osteoarthritis
         subjects affected / exposed
    1 / 545 (0.18%)
    4 / 890 (0.45%)
    5 / 1113 (0.45%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Spinal column stenosis
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    1 / 181 (0.55%)
    0 / 150 (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
    Acute sinusitis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Appendicitis
         subjects affected / exposed
    2 / 545 (0.37%)
    2 / 890 (0.22%)
    4 / 1113 (0.36%)
    2 / 181 (1.10%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    0 / 181 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Cellulitis
         subjects affected / exposed
    0 / 545 (0.00%)
    2 / 890 (0.22%)
    2 / 1113 (0.18%)
    1 / 181 (0.55%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Chronic sinusitis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Chronic tonsillitis
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 890 (0.00%)
    0 / 1113 (0.00%)
    1 / 181 (0.55%)
    0 / 150 (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
    Device related infection
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Diverticulitis
         subjects affected / exposed
    3 / 545 (0.55%)
    1 / 890 (0.11%)
    4 / 1113 (0.36%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    1 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Epididymitis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder empyema
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Graft infection
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Hepatitis A
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Implant site infection
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oophoritis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Osteomyelitis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Peritonitis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 545 (0.18%)
    4 / 890 (0.45%)
    5 / 1113 (0.45%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Postoperative wound infection
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Sepsis
         subjects affected / exposed
    0 / 545 (0.00%)
    4 / 890 (0.45%)
    4 / 1113 (0.36%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Sinusitis
         subjects affected / exposed
    1 / 545 (0.18%)
    1 / 890 (0.11%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tick-borne viral encephalitis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Tonsillitis
         subjects affected / exposed
    2 / 545 (0.37%)
    2 / 890 (0.22%)
    4 / 1113 (0.36%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
    4 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 545 (0.18%)
    1 / 890 (0.11%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral pericarditis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 890 (0.00%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 890 (0.11%)
    1 / 1113 (0.09%)
    0 / 181 (0.00%)
    0 / 150 (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
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 545 (0.18%)
    1 / 890 (0.11%)
    2 / 1113 (0.18%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    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
    		 Any AIN457 150 mg Any AIN457 300 mg Any AIN457 dose AIN457 300 mg (Core)- Placebo AIN457 150 mg (Core)- Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    386 / 545 (70.83%)
    679 / 890 (76.29%)
    889 / 1113 (79.87%)
    86 / 181 (47.51%)
    75 / 150 (50.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    42 / 545 (7.71%)
    83 / 890 (9.33%)
    119 / 1113 (10.69%)
    6 / 181 (3.31%)
    5 / 150 (3.33%)
         occurrences all number
    48
    98
    146
    6
    5
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    24 / 545 (4.40%)
    45 / 890 (5.06%)
    65 / 1113 (5.84%)
    2 / 181 (1.10%)
    2 / 150 (1.33%)
         occurrences all number
    35
    72
    107
    2
    2
    Pyrexia
         subjects affected / exposed
    7 / 545 (1.28%)
    24 / 890 (2.70%)
    31 / 1113 (2.79%)
    2 / 181 (1.10%)
    0 / 150 (0.00%)
         occurrences all number
    9
    30
    39
    2
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    8 / 545 (1.47%)
    19 / 890 (2.13%)
    27 / 1113 (2.43%)
    1 / 181 (0.55%)
    2 / 150 (1.33%)
         occurrences all number
    9
    20
    29
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    27 / 545 (4.95%)
    43 / 890 (4.83%)
    66 / 1113 (5.93%)
    4 / 181 (2.21%)
    1 / 150 (0.67%)
         occurrences all number
    36
    47
    83
    4
    1
    Oropharyngeal pain
         subjects affected / exposed
    23 / 545 (4.22%)
    42 / 890 (4.72%)
    65 / 1113 (5.84%)
    3 / 181 (1.66%)
    3 / 150 (2.00%)
         occurrences all number
    25
    47
    72
    4
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 545 (1.47%)
    20 / 890 (2.25%)
    28 / 1113 (2.52%)
    1 / 181 (0.55%)
    1 / 150 (0.67%)
         occurrences all number
    9
    25
    34
    1
    1
    Depression
         subjects affected / exposed
    14 / 545 (2.57%)
    10 / 890 (1.12%)
    24 / 1113 (2.16%)
    2 / 181 (1.10%)
    2 / 150 (1.33%)
         occurrences all number
    15
    12
    27
    2
    2
    Insomnia
         subjects affected / exposed
    11 / 545 (2.02%)
    20 / 890 (2.25%)
    30 / 1113 (2.70%)
    2 / 181 (1.10%)
    2 / 150 (1.33%)
         occurrences all number
    13
    26
    39
    2
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 545 (2.39%)
    8 / 890 (0.90%)
    21 / 1113 (1.89%)
    1 / 181 (0.55%)
    1 / 150 (0.67%)
         occurrences all number
    14
    11
    25
    1
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    9 / 545 (1.65%)
    22 / 890 (2.47%)
    31 / 1113 (2.79%)
    2 / 181 (1.10%)
    1 / 150 (0.67%)
         occurrences all number
    11
    25
    36
    2
    1
    Laceration
         subjects affected / exposed
    9 / 545 (1.65%)
    16 / 890 (1.80%)
    25 / 1113 (2.25%)
    0 / 181 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    9
    18
    27
    0
    1
    Ligament sprain
         subjects affected / exposed
    13 / 545 (2.39%)
    21 / 890 (2.36%)
    34 / 1113 (3.05%)
    2 / 181 (1.10%)
    1 / 150 (0.67%)
         occurrences all number
    13
    26
    39
    2
    1
    Muscle strain
         subjects affected / exposed
    9 / 545 (1.65%)
    17 / 890 (1.91%)
    25 / 1113 (2.25%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences all number
    9
    23
    32
    1
    0
    Procedural pain
         subjects affected / exposed
    8 / 545 (1.47%)
    21 / 890 (2.36%)
    29 / 1113 (2.61%)
    0 / 181 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    10
    24
    34
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    36 / 545 (6.61%)
    87 / 890 (9.78%)
    116 / 1113 (10.42%)
    2 / 181 (1.10%)
    4 / 150 (2.67%)
         occurrences all number
    64
    158
    222
    3
    7
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    11 / 545 (2.02%)
    15 / 890 (1.69%)
    25 / 1113 (2.25%)
    1 / 181 (0.55%)
    2 / 150 (1.33%)
         occurrences all number
    12
    18
    30
    1
    2
    Diarrhoea
         subjects affected / exposed
    29 / 545 (5.32%)
    53 / 890 (5.96%)
    81 / 1113 (7.28%)
    5 / 181 (2.76%)
    3 / 150 (2.00%)
         occurrences all number
    36
    64
    100
    7
    3
    Gastritis
         subjects affected / exposed
    11 / 545 (2.02%)
    21 / 890 (2.36%)
    31 / 1113 (2.79%)
    0 / 181 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    12
    22
    34
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    12 / 545 (2.20%)
    25 / 890 (2.81%)
    37 / 1113 (3.32%)
    0 / 181 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    12
    27
    39
    0
    1
    Nausea
         subjects affected / exposed
    9 / 545 (1.65%)
    15 / 890 (1.69%)
    24 / 1113 (2.16%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences all number
    10
    16
    26
    0
    0
    Toothache
         subjects affected / exposed
    10 / 545 (1.83%)
    33 / 890 (3.71%)
    43 / 1113 (3.86%)
    2 / 181 (1.10%)
    0 / 150 (0.00%)
         occurrences all number
    12
    38
    50
    2
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    5 / 545 (0.92%)
    19 / 890 (2.13%)
    23 / 1113 (2.07%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences all number
    5
    31
    36
    0
    0
    Eczema
         subjects affected / exposed
    8 / 545 (1.47%)
    34 / 890 (3.82%)
    41 / 1113 (3.68%)
    2 / 181 (1.10%)
    0 / 150 (0.00%)
         occurrences all number
    13
    42
    55
    3
    0
    Pruritus
         subjects affected / exposed
    11 / 545 (2.02%)
    24 / 890 (2.70%)
    34 / 1113 (3.05%)
    3 / 181 (1.66%)
    2 / 150 (1.33%)
         occurrences all number
    16
    27
    43
    3
    2
    Psoriasis
         subjects affected / exposed
    14 / 545 (2.57%)
    39 / 890 (4.38%)
    51 / 1113 (4.58%)
    3 / 181 (1.66%)
    1 / 150 (0.67%)
         occurrences all number
    17
    43
    60
    3
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    47 / 545 (8.62%)
    80 / 890 (8.99%)
    124 / 1113 (11.14%)
    13 / 181 (7.18%)
    8 / 150 (5.33%)
         occurrences all number
    65
    93
    158
    14
    9
    Back pain
         subjects affected / exposed
    40 / 545 (7.34%)
    76 / 890 (8.54%)
    114 / 1113 (10.24%)
    5 / 181 (2.76%)
    4 / 150 (2.67%)
         occurrences all number
    45
    89
    134
    5
    5
    Musculoskeletal pain
         subjects affected / exposed
    14 / 545 (2.57%)
    19 / 890 (2.13%)
    33 / 1113 (2.96%)
    0 / 181 (0.00%)
    0 / 150 (0.00%)
         occurrences all number
    14
    21
    35
    0
    0
    Myalgia
         subjects affected / exposed
    10 / 545 (1.83%)
    22 / 890 (2.47%)
    32 / 1113 (2.88%)
    1 / 181 (0.55%)
    3 / 150 (2.00%)
         occurrences all number
    11
    27
    38
    1
    3
    Pain in extremity
         subjects affected / exposed
    20 / 545 (3.67%)
    29 / 890 (3.26%)
    49 / 1113 (4.40%)
    2 / 181 (1.10%)
    2 / 150 (1.33%)
         occurrences all number
    22
    34
    56
    3
    2
    Psoriatic arthropathy
         subjects affected / exposed
    11 / 545 (2.02%)
    38 / 890 (4.27%)
    47 / 1113 (4.22%)
    6 / 181 (3.31%)
    8 / 150 (5.33%)
         occurrences all number
    11
    42
    53
    6
    9
    Tendonitis
         subjects affected / exposed
    5 / 545 (0.92%)
    23 / 890 (2.58%)
    28 / 1113 (2.52%)
    1 / 181 (0.55%)
    1 / 150 (0.67%)
         occurrences all number
    6
    23
    29
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    31 / 545 (5.69%)
    63 / 890 (7.08%)
    92 / 1113 (8.27%)
    3 / 181 (1.66%)
    3 / 150 (2.00%)
         occurrences all number
    38
    89
    127
    3
    3
    Conjunctivitis
         subjects affected / exposed
    10 / 545 (1.83%)
    30 / 890 (3.37%)
    38 / 1113 (3.41%)
    1 / 181 (0.55%)
    1 / 150 (0.67%)
         occurrences all number
    12
    36
    48
    2
    1
    Cystitis
         subjects affected / exposed
    10 / 545 (1.83%)
    23 / 890 (2.58%)
    31 / 1113 (2.79%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences all number
    10
    27
    37
    1
    0
    Folliculitis
         subjects affected / exposed
    13 / 545 (2.39%)
    18 / 890 (2.02%)
    31 / 1113 (2.79%)
    2 / 181 (1.10%)
    1 / 150 (0.67%)
         occurrences all number
    16
    19
    35
    2
    1
    Gastroenteritis
         subjects affected / exposed
    24 / 545 (4.40%)
    35 / 890 (3.93%)
    59 / 1113 (5.30%)
    2 / 181 (1.10%)
    3 / 150 (2.00%)
         occurrences all number
    28
    43
    71
    2
    3
    Herpes zoster
         subjects affected / exposed
    3 / 545 (0.55%)
    25 / 890 (2.81%)
    27 / 1113 (2.43%)
    0 / 181 (0.00%)
    2 / 150 (1.33%)
         occurrences all number
    3
    25
    28
    0
    2
    Influenza
         subjects affected / exposed
    24 / 545 (4.40%)
    54 / 890 (6.07%)
    78 / 1113 (7.01%)
    6 / 181 (3.31%)
    4 / 150 (2.67%)
         occurrences all number
    24
    57
    81
    7
    4
    Nasopharyngitis
         subjects affected / exposed
    145 / 545 (26.61%)
    271 / 890 (30.45%)
    375 / 1113 (33.69%)
    21 / 181 (11.60%)
    17 / 150 (11.33%)
         occurrences all number
    280
    548
    828
    29
    23
    Oral candidiasis
         subjects affected / exposed
    7 / 545 (1.28%)
    22 / 890 (2.47%)
    29 / 1113 (2.61%)
    0 / 181 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    10
    40
    50
    0
    1
    Oral herpes
         subjects affected / exposed
    12 / 545 (2.20%)
    25 / 890 (2.81%)
    36 / 1113 (3.23%)
    2 / 181 (1.10%)
    2 / 150 (1.33%)
         occurrences all number
    19
    39
    58
    2
    2
    Pharyngitis
         subjects affected / exposed
    18 / 545 (3.30%)
    38 / 890 (4.27%)
    55 / 1113 (4.94%)
    3 / 181 (1.66%)
    1 / 150 (0.67%)
         occurrences all number
    20
    62
    82
    5
    1
    Rhinitis
         subjects affected / exposed
    11 / 545 (2.02%)
    30 / 890 (3.37%)
    38 / 1113 (3.41%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences all number
    13
    36
    49
    1
    0
    Sinusitis
         subjects affected / exposed
    18 / 545 (3.30%)
    51 / 890 (5.73%)
    64 / 1113 (5.75%)
    3 / 181 (1.66%)
    4 / 150 (2.67%)
         occurrences all number
    20
    71
    91
    3
    4
    Tinea pedis
         subjects affected / exposed
    9 / 545 (1.65%)
    29 / 890 (3.26%)
    38 / 1113 (3.41%)
    2 / 181 (1.10%)
    0 / 150 (0.00%)
         occurrences all number
    10
    34
    44
    2
    0
    Tonsillitis
         subjects affected / exposed
    19 / 545 (3.49%)
    31 / 890 (3.48%)
    49 / 1113 (4.40%)
    3 / 181 (1.66%)
    6 / 150 (4.00%)
         occurrences all number
    21
    34
    55
    3
    6
    Tooth infection
         subjects affected / exposed
    10 / 545 (1.83%)
    18 / 890 (2.02%)
    28 / 1113 (2.52%)
    1 / 181 (0.55%)
    0 / 150 (0.00%)
         occurrences all number
    10
    26
    36
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    52 / 545 (9.54%)
    119 / 890 (13.37%)
    153 / 1113 (13.75%)
    12 / 181 (6.63%)
    8 / 150 (5.33%)
         occurrences all number
    77
    228
    305
    14
    10
    Urinary tract infection
         subjects affected / exposed
    15 / 545 (2.75%)
    33 / 890 (3.71%)
    46 / 1113 (4.13%)
    2 / 181 (1.10%)
    3 / 150 (2.00%)
         occurrences all number
    18
    50
    68
    2
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    11 / 545 (2.02%)
    21 / 890 (2.36%)
    31 / 1113 (2.79%)
    2 / 181 (1.10%)
    0 / 150 (0.00%)
         occurrences all number
    23
    34
    57
    2
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    3 / 545 (0.55%)
    18 / 890 (2.02%)
    20 / 1113 (1.80%)
    0 / 181 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    3
    19
    22
    0
    1
    Hyperlipidaemia
         subjects affected / exposed
    11 / 545 (2.02%)
    9 / 890 (1.01%)
    20 / 1113 (1.80%)
    0 / 181 (0.00%)
    2 / 150 (1.33%)
         occurrences all number
    11
    11
    22
    0
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    11 / 545 (2.02%)
    18 / 890 (2.02%)
    29 / 1113 (2.61%)
    1 / 181 (0.55%)
    2 / 150 (1.33%)
         occurrences all number
    12
    21
    33
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2014
    The purpose of this amendment was to provide continued treatment for patients in the trial for an additional 104 Weeks (or overall up to four years of treatment in the extension) or until the drug was commercially available in the market in the country of participation, whichever occurred first. This extension of treatment allowed for safety, tolerability, and efficacy data to be collected from the participating patients for a longer time period.
    09 Sep 2014
    The purpose of this amendment was to clarify the wording for countries not selected for early trial termination when the drug was commercially available, this study continued up to the end of additional 104 Weeks of treatment. It also clarified a discrepancy in the Assessment Schedule that PK samples at Week 140 were collected for all patients and at Week 144 in case of relapse.
    29 Apr 2015
    Patients who completed treatment period and follow-up period were evaluated for 4 years regarding respective adverse events. However, patient who prematurely discontinued treatment were evaluated for less than 4 years.

    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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