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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, multicenter study of secukinumab to demonstrate the efficacy at 24 weeks and to assess the long term safety, tolerability and efficacy up to 2 years in patients with active psoriatic arthritis.

    Summary
    EudraCT number
    		 2011-000276-34
    Trial protocol
    		 CZ   SK   GB   DE   BG   PL   BE   IT  
    Global end of trial date
    08 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAIN457F2306
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01392326
    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,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Apr 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate that the efficacy of secukinumab75 or 150 mg at Week 24 was superior to placebo in patients with active PsA based on the proportion of patients achieving an ACR20 response.
    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
    08 Sep 2011
    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: 27
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Brazil: 16
    Country: Number of subjects enrolled
    Bulgaria: 12
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Czech Republic: 44
    Country: Number of subjects enrolled
    Germany: 48
    Country: Number of subjects enrolled
    United Kingdom: 37
    Country: Number of subjects enrolled
    Israel: 35
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Philippines: 66
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Russian Federation: 40
    Country: Number of subjects enrolled
    Singapore: 16
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Thailand: 30
    Country: Number of subjects enrolled
    United States: 133
    Worldwide total number of subjects
    606
    EEA total number of subjects
    198
    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)
    552
    From 65 to 84 years
    54
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A screening period running up to 4 weeks before randomization was used to assess eligibility followed by a treatment period of two years.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1
    Arm description
    		 Secukinumab i.v. (10 mg/kg) at baseline, Weeks 2 and 4, then secukinumab 75 mg s.c. starting at Week 8 and injected every 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AIN457
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Secukinumab (75 mg)

    Arm title
    		 Group 2
    Arm description
    		 Secukinumab i.v. (10 mg/kg) at baseline, Weeks 2 and 4, then secukinumab 150 mg s.c. starting at Week 8 and injected every 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AIN457
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Secukinumab (150 mg)

    Arm title
    		 Group 3
    Arm description
    		 Placebo i.v. at baseline, Weeks 2 and 4, then placebo s.c. starting at Week 8 and Week 12. Patients on placebo who were responders remained on placebo until week 24. At Week 24, these patients received either secukinumab 75 or 150 mg every 4 weeks, regardless of responder status (as dictated by the re-randomization). • Patients on placebo who were non-responders were to be re-randomized (1:1) at Week 16 to receive either secukinumab 75 mg or 150 mg s.c. every 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Matching Placebo

    Number of subjects in period 1
    		Group 1 Group 2 Group 3
    Started
    202
    202
    202
    Completed
    155
    167
    154
    Not completed
    47
    35
    48
         Adverse event, serious fatal
    2
    -
    -
         Consent withdrawn by subject
    12
    11
    15
         Physician decision
    7
    5
    2
         Adverse event, non-fatal
    9
    6
    11
         Pregnancy
    -
    -
    1
         Lost to follow-up
    1
    3
    4
         Lack of efficacy
    14
    10
    15
         Protocol deviation
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Secukinumab i.v. (10 mg/kg) at baseline, Weeks 2 and 4, then secukinumab 75 mg s.c. starting at Week 8 and injected every 4 weeks

    Reporting group title
    Group 2
    Reporting group description
    		 Secukinumab i.v. (10 mg/kg) at baseline, Weeks 2 and 4, then secukinumab 150 mg s.c. starting at Week 8 and injected every 4 weeks

    Reporting group title
    Group 3
    Reporting group description
    		 Placebo i.v. at baseline, Weeks 2 and 4, then placebo s.c. starting at Week 8 and Week 12. Patients on placebo who were responders remained on placebo until week 24. At Week 24, these patients received either secukinumab 75 or 150 mg every 4 weeks, regardless of responder status (as dictated by the re-randomization). • Patients on placebo who were non-responders were to be re-randomized (1:1) at Week 16 to receive either secukinumab 75 mg or 150 mg s.c. every 4 weeks.

    Reporting group values
    		 Group 1 Group 2 Group 3 Total
    Number of subjects
    		 202 202 202 606
    Age Categorical
    Units: participants
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 180 180 192 552
        >=65 years
    		 22 22 10 54
    Gender, Male/Female
    Units: participants
        Female
    		 118 106 106 330
        Male
    		 84 96 96 276

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Secukinumab i.v. (10 mg/kg) at baseline, Weeks 2 and 4, then secukinumab 75 mg s.c. starting at Week 8 and injected every 4 weeks

    Reporting group title
    Group 2
    Reporting group description
    		 Secukinumab i.v. (10 mg/kg) at baseline, Weeks 2 and 4, then secukinumab 150 mg s.c. starting at Week 8 and injected every 4 weeks

    Reporting group title
    Group 3
    Reporting group description
    		 Placebo i.v. at baseline, Weeks 2 and 4, then placebo s.c. starting at Week 8 and Week 12. Patients on placebo who were responders remained on placebo until week 24. At Week 24, these patients received either secukinumab 75 or 150 mg every 4 weeks, regardless of responder status (as dictated by the re-randomization). • Patients on placebo who were non-responders were to be re-randomized (1:1) at Week 16 to receive either secukinumab 75 mg or 150 mg s.c. every 4 weeks.

    Primary: Proportion of patients achieving ACR20 response criteria on secukinumab 75 or 150 mg vs. placebo

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    End point title
    		 Proportion of patients achieving ACR20 response criteria on secukinumab 75 or 150 mg vs. placebo
    End point description
    A patient will be considered as responder according the ACR20 criteria if she/he has at least 20 % improvement in the two following measures:Tender joint count,Swollen joint count and at least 3 of the following 5 measures: Patient's assessment of PsA pain, Patient's global assessment disease activity,Physician's global assessment of disease activity, Health Assessment Questionnaire- Disability Index (HAQ-DI©) score ,Acute phase reactant (hsCRP or ESR)
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    202
    202
    202
    Units: % ACR 20 responders
        number (not applicable)
    50
    50
    17.3
    Statistical analysis title
    		 Patients acheiving ACR 20 response
    Comparison groups
    Group 1 v Group 3
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.46
         upper limit
    		 8.85
    Statistical analysis title
    		 Patients acheiving ACR 20 response
    Comparison groups
    Group 2 v Group 3
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.37
         upper limit
    		 8.62

    Secondary: Proportion of subjects achieving a PASI75 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis at baseline

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    End point title
    		 Proportion of subjects achieving a PASI75 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis at baseline
    End point description
    A 75% reduction in the Psoriasis Area and Severity Index (PASI) score (PASI 75) is the current benchmark of primary endpoints for most clinical trials with end points of psoriasis
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    108
    108
    109
    Units: % participants acheiving goal
        number (not applicable)
    64.8
    61.1
    8.3
    No statistical analyses for this end point

    Secondary: Proportion of subjects achieving a PASI90 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis at baseline

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    End point title
    		 Proportion of subjects achieving a PASI90 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis at baseline
    End point description
    A 90% reduction in the Psoriasis Area and Severity Index (PASI) score (PASI 90) is above the current benchmark of primary endpoints for most clinical trials with endpoints of psoriasis
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    108
    108
    109
    Units: % of participants acheiving goal
        number (not applicable)
    49.1
    45.4
    3.7
    No statistical analyses for this end point

    Secondary: Change from baseline in DAS28-CRP for secukinumab 75 or 150 mg

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    End point title
    		 Change from baseline in DAS28-CRP for secukinumab 75 or 150 mg
    End point description
    DAS-CRP values range from 2.0 to 10.0 , While higher values mean a higher disease activity. A DAS-CRP below the value of 2.6 is interpreted as Remission. The DAS-CRP uses 28 different joints for its calculation: proximal interphalangeal joints (10 joints) metacarpophalangeal joints (10) wrists (2) elbows (2) shoulders (2) knees (2) With the above mentioned parameters, DAS-CRP is calculated as: <math>DAS-CRP=0.56 \times \sqrt{TEN28} + 0.28 \times \sqrt{SW28} + 0.36 \times \ln(CRP+1) + 0.014 \times SA+0.96</math> With: TEN28: number of joints with tenderness upon touching SW28: number of swollen joints CRP: C-reactive Protein SA: subjective assessment of disease activity by the patient during the preceding 7 days on a scale between 0 and 100 ("0":no activity, "100": highest activity possible)
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    202
    202
    202
    Units: units on scale
        least squares mean (standard error)
    -1.67 ± 0.085
    -1.62 ± 0.084
    -0.77 ± 0.123
    No statistical analyses for this end point

    Secondary: Change from baseline in SF36-PCS for secukinumab 75 or 150 mg

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    End point title
    		 Change from baseline in SF36-PCS for secukinumab 75 or 150 mg
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    202
    202
    202
    Units: units on scale
        least squares mean (standard error)
    5.41 ± 0.524
    5.91 ± 0.525
    1.82 ± 0.715
    No statistical analyses for this end point

    Secondary: Change from baseline in HAQ-DI for secukinumab 75 or 150 mg

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    End point title
    		 Change from baseline in HAQ-DI for secukinumab 75 or 150 mg
    End point description
    HAQ-DI score change from baseline using MMRM
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    202
    202
    202
    Units: units on a scale
        least squares mean (standard error)
    -0.41 ± 0.036
    -0.4 ± 0.036
    -0.17 ± 0.047
    No statistical analyses for this end point

    Secondary: Proportion of patients achieving ACR50 response criteria on secukinumab 75 or 150 mg vs. placebo

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    End point title
    		 Proportion of patients achieving ACR50 response criteria on secukinumab 75 or 150 mg vs. placebo
    End point description
    ACR50 = 50 % improvement in at least 3 of the 5 measures( Patient's assessment of pain, Patient's global assessment of disease activity, Physician's global assessment of disease activity, Health Assessment Questionnaire (HAQ©) score, C-reactive protein (CRP)/Erythrocyte Sedimentation Rate (ESR) and 50 % improvement in the swollen and tender joint count.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    202
    202
    202
    Units: % change
        number (not applicable)
    30.7
    34.7
    7.4
    No statistical analyses for this end point

    Secondary: Change from baseline for joint/bone structural damage (van der Heijde modified total Sharp score) for secukinumab 75 and 150 mg (pooled doses)

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    End point title
    		 Change from baseline for joint/bone structural damage (van der Heijde modified total Sharp score) for secukinumab 75 and 150 mg (pooled doses)
    End point description
    Joint structural damage change from baseline at Week 24 using non-parametric ANCOVA, Linear extrapolation. Estimate (for the difference in mean), SE are from a non-parametric ANCOVA model with the change from baseline van der Heijde total modified Sharp score as the dependent variable, treatment and randomization stratum (TNFa status -naive or IR ) as factors, and weight and baseline van der Heijde total modified Sharp score as covariates
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    202
    202
    202
    Units: units on a scale
        arithmetic mean (standard error)
    0.02 ± 0.22
    0.13 ± 0.2
    0.57 ± 0.2
    No statistical analyses for this end point

    Secondary: Proportion of patients with dactylitis in the subset of subjects who have dactylitis at baseline

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    End point title
    		 Proportion of patients with dactylitis in the subset of subjects who have dactylitis at baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    104
    104
    116
    Units: % of baseline
        number (not applicable)
    43.3
    51.9
    84.5
    No statistical analyses for this end point

    Secondary: Proportion of patients with enthesitis in the subset of subjects who have enthesitis at baseline

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    End point title
    		 Proportion of patients with enthesitis in the subset of subjects who have enthesitis at baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    129
    126
    102
    Units: % participants
        number (not applicable)
    51.2
    54
    87.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Any AIN457 75 mg
    Reporting group description
    		 Secukinumab (75mg)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo match (for 75 and 150 mg)

    Reporting group title
    Any AIN457 150 mg
    Reporting group description
    		 Secukinumab (150 mg)

    Serious adverse events
    		 Any AIN457 75 mg Placebo Any AIN457 150 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 292 (10.96%)
    11 / 202 (5.45%)
    51 / 295 (17.29%)
         number of deaths (all causes)
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 202 (0.50%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleomorphic adenoma
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schwannoma
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 202 (0.50%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 202 (0.50%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemothorax
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 202 (0.50%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 202 (0.50%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Comminuted fracture
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin abrasion
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic liver injury
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 202 (0.50%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Intracranial venous sinus thrombosis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombotic stroke
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Normochromic normocytic anaemia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Ocular myasthenia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 292 (0.34%)
    1 / 202 (0.50%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral hernia
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 202 (0.50%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 202 (0.50%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic hepatitis
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rosacea
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 202 (0.50%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 292 (0.34%)
    1 / 202 (0.50%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scoliosis
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatitis Escherichia coli
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash pustular
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 202 (0.50%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Typhoid fever
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 202 (0.00%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 292 (0.00%)
    0 / 202 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Any AIN457 75 mg Placebo Any AIN457 150 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    175 / 292 (59.93%)
    66 / 202 (32.67%)
    183 / 295 (62.03%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 292 (7.19%)
    5 / 202 (2.48%)
    18 / 295 (6.10%)
         occurrences all number
    21
    6
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 292 (9.25%)
    7 / 202 (3.47%)
    25 / 295 (8.47%)
         occurrences all number
    39
    8
    38
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    21 / 292 (7.19%)
    6 / 202 (2.97%)
    21 / 295 (7.12%)
         occurrences all number
    31
    7
    27
    Nausea
         subjects affected / exposed
    16 / 292 (5.48%)
    2 / 202 (0.99%)
    11 / 295 (3.73%)
         occurrences all number
    19
    2
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 292 (4.79%)
    6 / 202 (2.97%)
    17 / 295 (5.76%)
         occurrences all number
    16
    9
    19
    Oropharyngeal pain
         subjects affected / exposed
    15 / 292 (5.14%)
    4 / 202 (1.98%)
    11 / 295 (3.73%)
         occurrences all number
    22
    5
    14
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    22 / 292 (7.53%)
    1 / 202 (0.50%)
    11 / 295 (3.73%)
         occurrences all number
    22
    1
    11
    Musculoskeletal and connective tissue disorders
    Psoriatic arthropathy
         subjects affected / exposed
    15 / 292 (5.14%)
    2 / 202 (0.99%)
    14 / 295 (4.75%)
         occurrences all number
    18
    2
    17
    Back pain
         subjects affected / exposed
    29 / 292 (9.93%)
    2 / 202 (0.99%)
    22 / 295 (7.46%)
         occurrences all number
    35
    2
    25
    Arthralgia
         subjects affected / exposed
    20 / 292 (6.85%)
    3 / 202 (1.49%)
    17 / 295 (5.76%)
         occurrences all number
    32
    3
    21
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    14 / 292 (4.79%)
    6 / 202 (2.97%)
    21 / 295 (7.12%)
         occurrences all number
    17
    7
    26
    Nasopharyngitis
         subjects affected / exposed
    61 / 292 (20.89%)
    11 / 202 (5.45%)
    54 / 295 (18.31%)
         occurrences all number
    106
    12
    99
    Gastroenteritis
         subjects affected / exposed
    8 / 292 (2.74%)
    2 / 202 (0.99%)
    20 / 295 (6.78%)
         occurrences all number
    11
    2
    25
    Sinusitis
         subjects affected / exposed
    10 / 292 (3.42%)
    4 / 202 (1.98%)
    16 / 295 (5.42%)
         occurrences all number
    16
    4
    17
    Urinary tract infection
         subjects affected / exposed
    14 / 292 (4.79%)
    2 / 202 (0.99%)
    17 / 295 (5.76%)
         occurrences all number
    17
    2
    21
    Upper respiratory tract infection
         subjects affected / exposed
    52 / 292 (17.81%)
    12 / 202 (5.94%)
    60 / 295 (20.34%)
         occurrences all number
    73
    13
    90
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    11 / 292 (3.77%)
    5 / 202 (2.48%)
    15 / 295 (5.08%)
         occurrences all number
    12
    5
    15

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Aug 2011
    This protocol amendment is issued to clarify discrepancies in the protocol. However, none of the changes has an impact for the conduct of the trial or the patient’s treatment. Wording on the subject number for re-screened subject was removed. Subject will be tracked using a unique subject identifier, that will be applied within the database but not visible for the investigator and therefore the sentence was misleading. The section ‘Serum biomarkers related to targeted pathway’ had been included as a subsection of ‘Pharmacogenetics,’ but Serum biomarkers should be a separate section This is now corrected. Furthermore, a Sample Log for serum biomarkers is now included in this section. Additionally, we took the opportunity of this protocol amendment to correct typographical and formatting errors, and to clarify certain wordings.
    18 Dec 2012
    This protocol amendment is issued to update sections of the data analysis plan, specifically to update how missing values are handled. The guidance language for study treatment interruptions and discontinuation has been clarified. The notable laboratory values and guidance for subject observation post study treatment administration have been aligned with the wording used in all current secukinumab arthritis studies. None of the changes made are due to safety concerns and none of the changes have impact on the conduct of the trial or alterin any way the treatment of study subjects. The wording of various sub-sections to “Data analysis” (Section 9) have been amended to reflect the rationale given above. Additionally, this protocol amendment includes the correction of typographical and formatting errors, and clarification of the wording in certain sections.
    06 Dec 2013
    To expand the statistical hierarchy (primary plus ranked secondary variables) to include more endpoints which are relevant to determining the overall therapeutic value of a therapy for PsA. These endpoints include but are not limited to PASI75, PASI90, DAS28- CRP, HAQ-DI, SF-36, dactylitis and enthesitis. Psoriatic arthritis (PsA) is a multifaceted chronic disabling disease that can present as different clinical phenotypes: peripheral arthritis, axial disease, skin and nail disease, dactylitis, and enthesitis, and hence defining outcome measures has been a challenge. In addition, the analysis is changed to include all subjects in Full Analysis Set (FAS) which includes TNFα inhibitor naïve as well as TNFα inhibitor inadequate responders (TNF-IR) rather than focusing only on the subset of subjects who are TNFα inhibitor naïve, as the FAS would be more representative of the general population of PsA patients. As the primary endpoint is at Week 24 and the analysis will be carried out after all subjects have completed Week 52 visit, there is no longer a need for the sponsor to be blinded past this time point. To mention only women of child bearing potential will undergo routine urine pregnancy tests (UPT). Thus this excludes postmenopausal women apart from sterile women from undergoing frequent UPT. This has been amended to avoid unnecessary UPT burden for women with confirmed menopause. None of the changes made are due to safety concerns and none of the changes have an impact on the conduct of the trial or alter in any way the treatment of study subjects.

    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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