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    Clinical Trial Results:
    A phase III, randomized, double-blind, placebo-controlled multicenter study of subcutaneous secukinumab (150 mg) in pre-filled syringe, with or without loading regimen, to demonstrate efficacy, safety and tolerability up to 2 years in patients with active psoriatic arthritis (FUTURE 4)

    Summary
    EudraCT number
    		 2014-003849-10
    Trial protocol
    		 SE   CZ   BE   BG   DE   GB   PL   FR   IT  
    Global end of trial date
    19 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Nov 2018
    First version publication date
    24 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAIN457F2336
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02294227
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    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 Pharmaceuticals, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    19 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate that the efficacy of secukinumab 150 mg sc, with or without loading regimen, at Week 16 was superior to placebo based on proportion of patients achieving American College of Rheumatology 20 (ACR20) response in patients with active PsA. The primary objective was reported in the CAIN457F2336 PsA Interim analyses at Week 52 CSR dated 14-Jun-2017.
    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
    29 May 2015
    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
    Australia: 35
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Czech Republic: 51
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 65
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Poland: 62
    Country: Number of subjects enrolled
    Russian Federation: 29
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 44
    Worldwide total number of subjects
    334
    EEA total number of subjects
    219
    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)
    309
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 There were 341 patients originally randomized to one of 2 trearment groups. Seven placebo patients discontinued before week 16 an therefore not switched to treatment. Only 334 patients received treatment.

    Pre-assignment
    Screening details
    		 Participants were randomized 1:1:1.

    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
    		 Investigator, Monitor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Secukinumab 150 mg
    Arm description
    		 Secukinumab 150 mg s.c. with loading: Secukinumab 150 mg at Baseline, Weeks 1, 2 and 3, followed by dosing every four weeks starting at Week 4. After primary outcome evaluation, approval and implementation of Amendment 2 Secukinumab dose may have been escalated to 300 mg as judged appropriate by the investigator
    Arm type
    		 Experimental

    Investigational medicinal product name
    AIN457F
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    secukinumab 150 mg subcutaneous

    Arm title
    		 Secukinumab 150 mg No load
    Arm description
    		 Secukinumab 150 mg s.c. without loading: Secukinumab 150 mg at baseline, followed by dosing every four weeks starting at Week 4, with Placebo at Weeks 1, 2 and 3. After primary outcome evaluation, approval and implementation of Amendment 2 Secukinumab dose may have been escalated to 300 mg as judged appropriate by the investigator
    Arm type
    		 Experimental

    Investigational medicinal product name
    AIN457F
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 150 mg subcutaneous

    Arm title
    		 Placebo
    Arm description
    		 Placebo to Secukinumab at Baseline, Weeks 1, 2 and 3, followed by dosing every four weeks starting at Week 4 until Week 16/24, depending on patients responder status. From Week 16/24, patients were switched to Secukinumab 150 mg every four weeks. After primary outcome evaluation, approval and implementation of Amendment 2 Secukinumab dose may have been escalated to 300 mg as judged appropriate by the investigator
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    150 mg subcutaneous injection

    Number of subjects in period 1
    		Secukinumab 150 mg Secukinumab 150 mg No load Placebo
    Started
    114
    113
    107
    Completed
    89
    88
    95
    Not completed
    25
    25
    12
         Adverse event, serious fatal
    -
    -
    1
         Physician decision
    1
    2
    1
         Adverse event, non-fatal
    6
    8
    2
         Subject/Guardian Decision
    6
    3
    2
         Lost to follow-up
    1
    -
    -
         Lack of efficacy
    11
    12
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Secukinumab 150 mg
    Reporting group description
    		 Secukinumab 150 mg s.c. with loading: Secukinumab 150 mg at Baseline, Weeks 1, 2 and 3, followed by dosing every four weeks starting at Week 4. After primary outcome evaluation, approval and implementation of Amendment 2 Secukinumab dose may have been escalated to 300 mg as judged appropriate by the investigator

    Reporting group title
    Secukinumab 150 mg No load
    Reporting group description
    		 Secukinumab 150 mg s.c. without loading: Secukinumab 150 mg at baseline, followed by dosing every four weeks starting at Week 4, with Placebo at Weeks 1, 2 and 3. After primary outcome evaluation, approval and implementation of Amendment 2 Secukinumab dose may have been escalated to 300 mg as judged appropriate by the investigator

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to Secukinumab at Baseline, Weeks 1, 2 and 3, followed by dosing every four weeks starting at Week 4 until Week 16/24, depending on patients responder status. From Week 16/24, patients were switched to Secukinumab 150 mg every four weeks. After primary outcome evaluation, approval and implementation of Amendment 2 Secukinumab dose may have been escalated to 300 mg as judged appropriate by the investigator

    Reporting group values
    		 Secukinumab 150 mg Secukinumab 150 mg No load Placebo Total
    Number of subjects
    		 114 113 107 334
    Age categorical
    Actual number of subjects enrolled in the study by age category (Randomized analysis set)
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 106 102 101 309
        From 65-84 years
    		 8 11 6 25
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 48.3 ( 12.17 ) 50.4 ( 11.78 ) 48.5 ( 12.12 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 47 51 43 141
        Male
    		 67 62 64 193
    Race/Ethnicity, Customized
    Units: Subjects
        Asian|
    		 1 0 0 1
        White|
    		 113 113 107 333

    End points

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    End points reporting groups
    Reporting group title
    Secukinumab 150 mg
    Reporting group description
    		 Secukinumab 150 mg s.c. with loading: Secukinumab 150 mg at Baseline, Weeks 1, 2 and 3, followed by dosing every four weeks starting at Week 4. After primary outcome evaluation, approval and implementation of Amendment 2 Secukinumab dose may have been escalated to 300 mg as judged appropriate by the investigator

    Reporting group title
    Secukinumab 150 mg No load
    Reporting group description
    		 Secukinumab 150 mg s.c. without loading: Secukinumab 150 mg at baseline, followed by dosing every four weeks starting at Week 4, with Placebo at Weeks 1, 2 and 3. After primary outcome evaluation, approval and implementation of Amendment 2 Secukinumab dose may have been escalated to 300 mg as judged appropriate by the investigator

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to Secukinumab at Baseline, Weeks 1, 2 and 3, followed by dosing every four weeks starting at Week 4 until Week 16/24, depending on patients responder status. From Week 16/24, patients were switched to Secukinumab 150 mg every four weeks. After primary outcome evaluation, approval and implementation of Amendment 2 Secukinumab dose may have been escalated to 300 mg as judged appropriate by the investigator

    Subject analysis set title
    Placebo non-responder
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo to Secukinumab at Baseline, Weeks 1, 2 and 3, followed by dosing every four weeks starting at Week 4 until Week 16/24, depending on patients responder status. From Week 16/24, patients were switched to Secukinumab 150 mg every four weeks. After primary outcome evaluation, approval and implementation of Amendment 2 Secukinumab dose may have been escalated to 300 mg as judged appropriate by the investigator

    Primary: Number of participants with American College of Rheumatology 20 (ACR20) response

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    End point title
    		 Number of participants with American College of Rheumatology 20 (ACR20) response
    End point description
    The ACR20 response is defined by at least 20% decrease in the swollen and tender joint count, and at least 20% improvement in 3 of the following 5 criteria: Health Assessment Questionnaire – Diability Index, pain score on a visual analog scale, patient global assessment of disease activity, physician global assessment of disease activity and acute phase reactant [either erythrocyte sedimentation rate (ESR) or high sensitivity C-reactive protein (hsCRP)]. ACR20 is used to assess the efficacy of secukinumab, with or without loading, versus placebo.
    End point type
    Primary
    End point timeframe
    16 weeks
    End point values
    		 Secukinumab 150 mg Secukinumab 150 mg No load Placebo
    Number of subjects analysed
    114
    113
    107
    Units: Participants
    47
    45
    21
    Statistical analysis title
    		 ACR20 comparison between groups at week 16
    Comparison groups
    Secukinumab 150 mg v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.76
         upper limit
    		 5.97
    Statistical analysis title
    		 ACR20 comparison between groups at 16 weeks
    Statistical analysis description
    Secukinumab 150 mg No load
    Comparison groups
    Secukinumab 150 mg No load v Placebo
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.0003
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.66
         upper limit
    		 5.66

    Secondary: Disease Activity Score (DAS-C28-CRP) score change from baseline using MMRM at week 16

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    End point title
    		 Disease Activity Score (DAS-C28-CRP) score change from baseline using MMRM at week 16
    End point description
    DAS28-CRP score change from baseline using MMRM up to Week 16. DAS-CRP values range between 2.0 and 10. The higher the score, the higher the disease severity. n: Number of subjects with measures at both baseline and the corresponding post baseline visit.
    End point type
    Secondary
    End point timeframe
    week 16
    End point values
    		 Secukinumab 150 mg Secukinumab 150 mg No load Placebo
    Number of subjects analysed
    114
    113
    107
    Units: scores
        least squares mean (standard error)
    -0.98 ( 0.106 )
    -0.84 ( 0.106 )
    -0.21 ( 0.107 )
    No statistical analyses for this end point

    Secondary: Psoriatic Area and Severity Index 75 (PASI75)

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    End point title
    		 Psoriatic Area and Severity Index 75 (PASI75)
    End point description
    PASI is a measure of disease activity based on extent of the disease, severity of erythema, scaling and thickness in different body areas affected by psoriasis. PASI75 is an improvement in the PASI score of at least 75% compared to baseline. PASI75 is used to assess the efficacy of secukinumab, with or without loading, versus placebo. PASI75 response using non-responder imputation and rescue penalty up to Week 16
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 Secukinumab 150 mg Secukinumab 150 mg No load Placebo
    Number of subjects analysed
    55
    54
    62
    Units: participants
    29
    27
    5
    No statistical analyses for this end point

    Secondary: Short Form Health Survey Physical Component Score (SF-36-PCS)

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    End point title
    		 Short Form Health Survey Physical Component Score (SF-36-PCS) [1]
    End point description
    The SF-36-PCS is a 36 item questionnaire which measures Quality of Life across 8 domains (assessing both physical and mental health). Two overall summary scores, the Physical Component Summary (PCS) and Mental Component Summary (MCS) can be computed. SF-36-PCS is used to assess the efficacy of secukinumab, with or without loading, versus placebo.
    End point type
    Secondary
    End point timeframe
    16 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    		 Secukinumab 150 mg Secukinumab 150 mg No load Placebo non-responder
    Number of subjects analysed
    114
    113
    77
    Units: scores
        least squares mean (standard error)
    3.42 ( 0.5676 )
    3.44 ( 0.5678 )
    0.63 ( 0.586 )
    No statistical analyses for this end point

    Secondary: Number of participants with American College of Rheumatology 50 (ACR50)

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    End point title
    		 Number of participants with American College of Rheumatology 50 (ACR50)
    End point description
    The ACR50 response is defined by at least 50% decrease in the swollen and tender joint count, and at least 50% improvement in 3 of the following 5 criteria: Health Assessment Questionnaire, pain score on a visual analog scale, patient global assessment of disease activity, physician global assessment of disease activity and acute phase reactant [either erythrocyte sedimentation rate (ESR) or high sensitivity C-reactive protein (hsCRP)]. ACR50 is used to assess the efficacy of secukinumab, with or without loading, versus placebo. This table is the ACR50 response using non-responder imputation and rescue penalty up to Week 16
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 Secukinumab 150 mg Secukinumab 150 mg No load Placebo
    Number of subjects analysed
    114
    113
    107
    Units: participants
    26
    19
    7
    No statistical analyses for this end point

    Secondary: Number of participants with American College of Rheumatology 20 (ACR20) response

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    End point title
    		 Number of participants with American College of Rheumatology 20 (ACR20) response
    End point description
    The ACR20 response is defined by at least 20% decrease in the swollen and tender joint count, and at least 20% improvement in 3 of the following 5 criteria: Health Assessment Questionnaire – Diability Index, pain score on a visual analog scale, patient global assessment of disease activity, physician global assessment of disease activity and acute phase reactant [either erythrocyte sedimentation rate (ESR) or high sensitivity C-reactive protein (hsCRP)]. ACR20 is used to assess the efficacy of secukinumab, with or without loading, versus placebo
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Secukinumab 150 mg Secukinumab 150 mg No load Placebo
    Number of subjects analysed
    114
    113
    107
    Units: participants
    33
    26
    22
    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 are reported in this record from 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
    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
    Reporting group description
    		 Any AIN457

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Any AIN457 150 mg Any AIN457 300 mg Any AIN457 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    47 / 334 (14.07%)
    12 / 136 (8.82%)
    59 / 334 (17.66%)
    5 / 114 (4.39%)
         number of deaths (all causes)
    1
    1
    2
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal adenoma
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibroma
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 334 (0.30%)
    1 / 136 (0.74%)
    2 / 334 (0.60%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Undifferentiated sarcoma
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Immunosuppression
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device fastener issue
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 334 (0.30%)
    1 / 136 (0.74%)
    2 / 334 (0.60%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 334 (0.60%)
    0 / 136 (0.00%)
    2 / 334 (0.60%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 334 (0.30%)
    1 / 136 (0.74%)
    2 / 334 (0.60%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 334 (0.60%)
    0 / 136 (0.00%)
    2 / 334 (0.60%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervicogenic headache
         subjects affected / exposed
    0 / 334 (0.00%)
    0 / 136 (0.00%)
    0 / 334 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 334 (0.60%)
    0 / 136 (0.00%)
    2 / 334 (0.60%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 334 (0.00%)
    0 / 136 (0.00%)
    0 / 334 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis alcoholic
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric compression
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 334 (0.00%)
    0 / 136 (0.00%)
    0 / 334 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loose body in joint
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 334 (0.90%)
    0 / 136 (0.00%)
    3 / 334 (0.90%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriatic arthropathy
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 334 (0.00%)
    0 / 136 (0.00%)
    0 / 334 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 334 (0.00%)
    0 / 136 (0.00%)
    0 / 334 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 136 (0.74%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 136 (0.00%)
    1 / 334 (0.30%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    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 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    252 / 334 (75.45%)
    89 / 136 (65.44%)
    267 / 334 (79.94%)
    61 / 114 (53.51%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    28 / 334 (8.38%)
    2 / 136 (1.47%)
    30 / 334 (8.98%)
    4 / 114 (3.51%)
         occurrences all number
    28
    2
    30
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 334 (3.89%)
    3 / 136 (2.21%)
    16 / 334 (4.79%)
    2 / 114 (1.75%)
         occurrences all number
    15
    3
    18
    2
    Oedema peripheral
         subjects affected / exposed
    5 / 334 (1.50%)
    2 / 136 (1.47%)
    7 / 334 (2.10%)
    1 / 114 (0.88%)
         occurrences all number
    5
    3
    8
    1
    Pyrexia
         subjects affected / exposed
    11 / 334 (3.29%)
    1 / 136 (0.74%)
    12 / 334 (3.59%)
    1 / 114 (0.88%)
         occurrences all number
    12
    1
    13
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 334 (4.79%)
    0 / 136 (0.00%)
    16 / 334 (4.79%)
    2 / 114 (1.75%)
         occurrences all number
    19
    0
    19
    2
    Oropharyngeal pain
         subjects affected / exposed
    13 / 334 (3.89%)
    3 / 136 (2.21%)
    16 / 334 (4.79%)
    1 / 114 (0.88%)
         occurrences all number
    18
    3
    21
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 334 (2.10%)
    1 / 136 (0.74%)
    8 / 334 (2.40%)
    1 / 114 (0.88%)
         occurrences all number
    11
    1
    12
    1
    Hepatic enzyme increased
         subjects affected / exposed
    6 / 334 (1.80%)
    2 / 136 (1.47%)
    8 / 334 (2.40%)
    0 / 114 (0.00%)
         occurrences all number
    7
    2
    9
    0
    Weight increased
         subjects affected / exposed
    6 / 334 (1.80%)
    1 / 136 (0.74%)
    7 / 334 (2.10%)
    1 / 114 (0.88%)
         occurrences all number
    6
    1
    7
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    10 / 334 (2.99%)
    1 / 136 (0.74%)
    11 / 334 (3.29%)
    1 / 114 (0.88%)
         occurrences all number
    12
    1
    13
    1
    Fall
         subjects affected / exposed
    11 / 334 (3.29%)
    2 / 136 (1.47%)
    13 / 334 (3.89%)
    1 / 114 (0.88%)
         occurrences all number
    14
    2
    16
    1
    Limb injury
         subjects affected / exposed
    10 / 334 (2.99%)
    1 / 136 (0.74%)
    11 / 334 (3.29%)
    0 / 114 (0.00%)
         occurrences all number
    10
    2
    12
    0
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    3 / 334 (0.90%)
    3 / 136 (2.21%)
    6 / 334 (1.80%)
    0 / 114 (0.00%)
         occurrences all number
    3
    3
    6
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 334 (1.50%)
    0 / 136 (0.00%)
    5 / 334 (1.50%)
    3 / 114 (2.63%)
         occurrences all number
    6
    0
    6
    4
    Headache
         subjects affected / exposed
    25 / 334 (7.49%)
    5 / 136 (3.68%)
    30 / 334 (8.98%)
    10 / 114 (8.77%)
         occurrences all number
    36
    5
    41
    12
    Migraine
         subjects affected / exposed
    6 / 334 (1.80%)
    1 / 136 (0.74%)
    7 / 334 (2.10%)
    0 / 114 (0.00%)
         occurrences all number
    10
    1
    11
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    9 / 334 (2.69%)
    3 / 136 (2.21%)
    12 / 334 (3.59%)
    0 / 114 (0.00%)
         occurrences all number
    16
    3
    19
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    8 / 334 (2.40%)
    1 / 136 (0.74%)
    9 / 334 (2.69%)
    1 / 114 (0.88%)
         occurrences all number
    8
    1
    9
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 334 (2.99%)
    1 / 136 (0.74%)
    11 / 334 (3.29%)
    1 / 114 (0.88%)
         occurrences all number
    12
    1
    13
    1
    Diarrhoea
         subjects affected / exposed
    29 / 334 (8.68%)
    4 / 136 (2.94%)
    32 / 334 (9.58%)
    3 / 114 (2.63%)
         occurrences all number
    39
    4
    43
    3
    Dyspepsia
         subjects affected / exposed
    6 / 334 (1.80%)
    3 / 136 (2.21%)
    9 / 334 (2.69%)
    0 / 114 (0.00%)
         occurrences all number
    6
    3
    9
    0
    Nausea
         subjects affected / exposed
    19 / 334 (5.69%)
    2 / 136 (1.47%)
    21 / 334 (6.29%)
    6 / 114 (5.26%)
         occurrences all number
    22
    2
    24
    6
    Toothache
         subjects affected / exposed
    3 / 334 (0.90%)
    3 / 136 (2.21%)
    5 / 334 (1.50%)
    0 / 114 (0.00%)
         occurrences all number
    3
    3
    6
    0
    Vomiting
         subjects affected / exposed
    8 / 334 (2.40%)
    2 / 136 (1.47%)
    10 / 334 (2.99%)
    1 / 114 (0.88%)
         occurrences all number
    8
    2
    10
    1
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    6 / 334 (1.80%)
    2 / 136 (1.47%)
    8 / 334 (2.40%)
    0 / 114 (0.00%)
         occurrences all number
    6
    2
    8
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    7 / 334 (2.10%)
    0 / 136 (0.00%)
    7 / 334 (2.10%)
    2 / 114 (1.75%)
         occurrences all number
    7
    0
    7
    2
    Pruritus
         subjects affected / exposed
    6 / 334 (1.80%)
    2 / 136 (1.47%)
    8 / 334 (2.40%)
    1 / 114 (0.88%)
         occurrences all number
    6
    2
    8
    1
    Psoriasis
         subjects affected / exposed
    7 / 334 (2.10%)
    5 / 136 (3.68%)
    12 / 334 (3.59%)
    1 / 114 (0.88%)
         occurrences all number
    8
    5
    13
    1
    Rash
         subjects affected / exposed
    6 / 334 (1.80%)
    2 / 136 (1.47%)
    8 / 334 (2.40%)
    0 / 114 (0.00%)
         occurrences all number
    6
    2
    8
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 334 (3.29%)
    4 / 136 (2.94%)
    15 / 334 (4.49%)
    1 / 114 (0.88%)
         occurrences all number
    11
    4
    15
    2
    Back pain
         subjects affected / exposed
    14 / 334 (4.19%)
    2 / 136 (1.47%)
    15 / 334 (4.49%)
    2 / 114 (1.75%)
         occurrences all number
    17
    3
    20
    2
    Osteoarthritis
         subjects affected / exposed
    7 / 334 (2.10%)
    2 / 136 (1.47%)
    9 / 334 (2.69%)
    0 / 114 (0.00%)
         occurrences all number
    7
    2
    9
    0
    Pain in extremity
         subjects affected / exposed
    6 / 334 (1.80%)
    1 / 136 (0.74%)
    7 / 334 (2.10%)
    1 / 114 (0.88%)
         occurrences all number
    6
    1
    7
    1
    Psoriatic arthropathy
         subjects affected / exposed
    21 / 334 (6.29%)
    12 / 136 (8.82%)
    28 / 334 (8.38%)
    5 / 114 (4.39%)
         occurrences all number
    28
    18
    46
    5
    Rotator cuff syndrome
         subjects affected / exposed
    5 / 334 (1.50%)
    2 / 136 (1.47%)
    7 / 334 (2.10%)
    0 / 114 (0.00%)
         occurrences all number
    6
    2
    8
    0
    Spinal pain
         subjects affected / exposed
    6 / 334 (1.80%)
    1 / 136 (0.74%)
    7 / 334 (2.10%)
    0 / 114 (0.00%)
         occurrences all number
    8
    1
    9
    0
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 334 (0.00%)
    0 / 136 (0.00%)
    0 / 334 (0.00%)
    3 / 114 (2.63%)
         occurrences all number
    0
    0
    0
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    31 / 334 (9.28%)
    8 / 136 (5.88%)
    38 / 334 (11.38%)
    2 / 114 (1.75%)
         occurrences all number
    37
    10
    47
    2
    Cystitis
         subjects affected / exposed
    7 / 334 (2.10%)
    3 / 136 (2.21%)
    10 / 334 (2.99%)
    1 / 114 (0.88%)
         occurrences all number
    10
    4
    14
    1
    Furuncle
         subjects affected / exposed
    6 / 334 (1.80%)
    1 / 136 (0.74%)
    7 / 334 (2.10%)
    0 / 114 (0.00%)
         occurrences all number
    6
    1
    7
    0
    Gastroenteritis
         subjects affected / exposed
    15 / 334 (4.49%)
    5 / 136 (3.68%)
    19 / 334 (5.69%)
    3 / 114 (2.63%)
         occurrences all number
    15
    6
    21
    3
    Gastroenteritis viral
         subjects affected / exposed
    7 / 334 (2.10%)
    1 / 136 (0.74%)
    8 / 334 (2.40%)
    1 / 114 (0.88%)
         occurrences all number
    7
    1
    8
    1
    Gingivitis
         subjects affected / exposed
    6 / 334 (1.80%)
    1 / 136 (0.74%)
    7 / 334 (2.10%)
    2 / 114 (1.75%)
         occurrences all number
    7
    1
    8
    2
    Influenza
         subjects affected / exposed
    11 / 334 (3.29%)
    4 / 136 (2.94%)
    14 / 334 (4.19%)
    2 / 114 (1.75%)
         occurrences all number
    16
    6
    22
    2
    Laryngitis
         subjects affected / exposed
    5 / 334 (1.50%)
    3 / 136 (2.21%)
    8 / 334 (2.40%)
    1 / 114 (0.88%)
         occurrences all number
    6
    3
    9
    1
    Nasopharyngitis
         subjects affected / exposed
    86 / 334 (25.75%)
    21 / 136 (15.44%)
    96 / 334 (28.74%)
    16 / 114 (14.04%)
         occurrences all number
    135
    28
    163
    18
    Oral herpes
         subjects affected / exposed
    11 / 334 (3.29%)
    4 / 136 (2.94%)
    13 / 334 (3.89%)
    3 / 114 (2.63%)
         occurrences all number
    15
    5
    20
    3
    Pharyngitis
         subjects affected / exposed
    23 / 334 (6.89%)
    4 / 136 (2.94%)
    25 / 334 (7.49%)
    1 / 114 (0.88%)
         occurrences all number
    32
    5
    37
    1
    Pulpitis dental
         subjects affected / exposed
    8 / 334 (2.40%)
    2 / 136 (1.47%)
    10 / 334 (2.99%)
    0 / 114 (0.00%)
         occurrences all number
    8
    2
    10
    0
    Respiratory tract infection
         subjects affected / exposed
    10 / 334 (2.99%)
    2 / 136 (1.47%)
    11 / 334 (3.29%)
    2 / 114 (1.75%)
         occurrences all number
    12
    2
    14
    2
    Rhinitis
         subjects affected / exposed
    9 / 334 (2.69%)
    5 / 136 (3.68%)
    14 / 334 (4.19%)
    1 / 114 (0.88%)
         occurrences all number
    10
    5
    15
    1
    Sinusitis
         subjects affected / exposed
    29 / 334 (8.68%)
    11 / 136 (8.09%)
    34 / 334 (10.18%)
    1 / 114 (0.88%)
         occurrences all number
    41
    13
    54
    1
    Tonsillitis
         subjects affected / exposed
    10 / 334 (2.99%)
    6 / 136 (4.41%)
    14 / 334 (4.19%)
    0 / 114 (0.00%)
         occurrences all number
    13
    6
    19
    0
    Upper respiratory tract infection
         subjects affected / exposed
    48 / 334 (14.37%)
    11 / 136 (8.09%)
    55 / 334 (16.47%)
    6 / 114 (5.26%)
         occurrences all number
    67
    12
    79
    7
    Urinary tract infection
         subjects affected / exposed
    17 / 334 (5.09%)
    1 / 136 (0.74%)
    18 / 334 (5.39%)
    4 / 114 (3.51%)
         occurrences all number
    20
    1
    21
    4
    Viral infection
         subjects affected / exposed
    6 / 334 (1.80%)
    2 / 136 (1.47%)
    8 / 334 (2.40%)
    1 / 114 (0.88%)
         occurrences all number
    6
    2
    8
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    11 / 334 (3.29%)
    2 / 136 (1.47%)
    13 / 334 (3.89%)
    1 / 114 (0.88%)
         occurrences all number
    13
    2
    15
    1
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    9 / 334 (2.69%)
    1 / 136 (0.74%)
    9 / 334 (2.69%)
    4 / 114 (3.51%)
         occurrences all number
    9
    2
    11
    4
    Hypercholesterolaemia
         subjects affected / exposed
    13 / 334 (3.89%)
    4 / 136 (2.94%)
    17 / 334 (5.09%)
    1 / 114 (0.88%)
         occurrences all number
    13
    4
    17
    1
    Hyperlipidaemia
         subjects affected / exposed
    5 / 334 (1.50%)
    2 / 136 (1.47%)
    7 / 334 (2.10%)
    0 / 114 (0.00%)
         occurrences all number
    5
    2
    7
    0
    Vitamin D deficiency
         subjects affected / exposed
    6 / 334 (1.80%)
    1 / 136 (0.74%)
    7 / 334 (2.10%)
    0 / 114 (0.00%)
         occurrences all number
    6
    1
    7
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jun 2015
    Update to inclusion and exclusion criteria
    30 May 2016
    Exploratory endpoint added: up-titration

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

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