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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled study of secukinumab to demonstrate the efficacy at 24 weeks and to assess the safety, tolerability and long term efficacy up to 2 years in patients with active rheumatoid arthritis who have an inadequate response to anti-TNFα agents (CAIN457F2302) and A three year extension study to evaluate the long term efficacy, safety and tolerability of secukinumab in patients with active rheumatoid arthritis (CAIN457F2302E1)

    Summary
    EudraCT number
    		 2011-000275-13
    Trial protocol
    		 HU   GB   BE   IT  
    Global end of trial date
    26 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Jun 2016
    First version publication date
    10 Jun 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CAIN457F2302/CAIN457F2302E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01377012
    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
    26 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of core study CAIN457F2302 was to demonstrate that the efficacy of secukinumab 75 mg or 150 mg at Week 24 is superior to placebo in patients with active RA based on the proportion of patients achieving an ACR20 response. The primary objective of the extension study CAIN457F2302E1 was to evaluate the long term efficacy of secukinumab 150 mg with respect to ACR20, ACR50 and ACR70 response over time. However, This study was terminated early by the Sponsor (unrelated to safety) due to the results of study AIN457F2309, which indicated the efficacy of AIN457 was not comparable to the currently available RA treatment, abatacept, thus leading to closing of the AIN457 RA program
    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
    30 Aug 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: 48
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Colombia: 29
    Country: Number of subjects enrolled
    Guatemala: 31
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Hungary: 54
    Country: Number of subjects enrolled
    India: 49
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Japan: 154
    Country: Number of subjects enrolled
    Mexico: 73
    Country: Number of subjects enrolled
    Panama: 10
    Country: Number of subjects enrolled
    Thailand: 11
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    United States: 145
    Worldwide total number of subjects
    637
    EEA total number of subjects
    82
    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)
    535
    From 65 to 84 years
    102
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 At baseline, participants were randomized to 1 of 3 treatment groups. Placebo non- responders at week 16 were re-randomized to receive AIN457 75mg or AIN457 150mg. Placebo responders at Week16 were re-randomized to receive AIN457 75mg or AIN457 150mg at Week 24.

    Period 1
    Period 1 title
    Core Study
    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
    		 AIN457 10mg/kg-75mg
    Arm description
    		 Participants received AIN457 i.v. (10 mg/kg) at Baseline (BSL), Weeks 2 and 4 then AIN457 75 mg s.c. 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 and solution for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    secukinumab i.v. (10 mg/kg) at baseline, Weeks 2 and 4 then secukinumab 75mg every 4 weeks

    Arm title
    		 AIN457 10mg/kg-150mg
    Arm description
    		 Participants received AIN457 i.v. (10 mg/kg) at BSL, Weeks 2 and 4 then AIN457 150 mg s.c. 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 and solution for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    secukinumab i.v. (10 mg/kg) at baseline, Weeks 2 and 4 then secukinumab 150mg every 4 weeks

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching placebo to AIN457 until week 16 or week 24 based on responder status (>= 20% reduction in tender and swollen joint count). Non-responders were switched to active treatment at week 16. Responders were switched to active treatment at 24 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    placebo i.v. at baseline, Weeks 2 and 4 then placebo s.c. starting at Week 8 and injected every 4 weeks

    Number of subjects in period 1
    		AIN457 10mg/kg-75mg AIN457 10mg/kg-150mg Placebo
    Started
    210
    213
    214
    Completed
    76
    81
    80
    Not completed
    134
    132
    134
         Adverse event, serious fatal
    1
    1
    1
         Consent withdrawn by subject
    15
    23
    18
         Physician decision
    5
    4
    10
         No Longer require treatment
    -
    -
    1
         Technical problems
    1
    -
    -
         Adverse event, non-fatal
    10
    14
    13
         Pregnancy
    -
    -
    1
         Study terminated by sponsor
    47
    54
    46
         Non-Compliant with study treatment
    -
    -
    1
         Lost to follow-up
    7
    5
    4
         Protocol deviation
    7
    3
    2
         Lack of efficacy
    41
    28
    37
    Period 2
    Period 2 title
    Extension Study, weeks 104-260
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AIN457 10mg/kg-75mg
    Arm description
    		 Participants received AIN457 i.v. (10 mg/kg) at Baseline (BSL), Weeks 2 and 4 then AIN457 75 mg s.c. at Week 8 and injected every 4 weeks up to Week 100, then AIN457 150 mg s.c. starting at week 104
    Arm type
    		 Experimental

    Investigational medicinal product name
    secukinumab
    Investigational medicinal product code
    AIN457
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    secukinumab i.v. (10 mg/kg) at baseline, Weeks 2 and 4 then secukinumab 75 up to Week 100, then secukinumab 150 mg starting at Week 104

    Arm title
    		 AIN457 10mg/kg-150mg
    Arm description
    		 Participants received AIN457 i.v. (10 mg/kg) at BSL, Weeks 2 and 4 then AIN457 150 mg s.c. 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 and solution for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    secukinumab i.v. (10 mg/kg) at baseline, Weeks 2 and 4 then secukinumab 150mg every 4 weeks

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching placebo to AIN457 until week 16 or week 24 based on responder status (>= 20% reduction in tender and swollen joint count). Non-responders were switched to active treatment at week 16. Responders were switched to active treatment at week 24
    Arm type
    		 Placebo

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    placebo i.v. at baseline, Weeks 2 and 4 then placebo s.c. starting at Week 8 and injected every 4 weeks. injected every 4 weeks. Treatment was switched to active treatment at Week 16 or Week 24

    Number of subjects in period 2 [1]
    		AIN457 10mg/kg-75mg AIN457 10mg/kg-150mg Placebo
    Started
    57
    71
    68
    Completed
    0
    0
    0
    Not completed
    57
    71
    68
         Consent withdrawn by subject
    1
    -
    3
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    -
    2
    1
         Study terminated by sponsor
    52
    69
    63
         Lost to follow-up
    -
    -
    1
         Lack of efficacy
    3
    -
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: This study includes a core phase (CAIN457F2302) and extension phase (CAIN457F2302E1).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AIN457 10mg/kg-75mg
    Reporting group description
    		 Participants received AIN457 i.v. (10 mg/kg) at Baseline (BSL), Weeks 2 and 4 then AIN457 75 mg s.c. at Week 8 and injected every 4 weeks

    Reporting group title
    AIN457 10mg/kg-150mg
    Reporting group description
    		 Participants received AIN457 i.v. (10 mg/kg) at BSL, Weeks 2 and 4 then AIN457 150 mg s.c. at Week 8 and injected every 4 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo to AIN457 until week 16 or week 24 based on responder status (>= 20% reduction in tender and swollen joint count). Non-responders were switched to active treatment at week 16. Responders were switched to active treatment at 24 weeks

    Reporting group values
    		 AIN457 10mg/kg-75mg AIN457 10mg/kg-150mg Placebo Total
    Number of subjects
    		 210 213 214 637
    Age, Customized
    Units: Particpants
        In Utero
    		 0 0 0 0
        Preterm Newborn Infants
    		 0 0 0 0
        0-<28 days
    		 0 0 0 0
        28 days - <2 years
    		 0 0 0 0
        2 years - <12 years
    		 0 0 0 0
        12 years - <18 years
    		 0 0 0 0
        18 years - < 65 years
    		 177 176 182 535
        65 years - <85 years
    		 33 37 32 102
        >=85 years
    		 0 0 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 53.3 ± 12.27 53.2 ± 11.62 52.2 ± 11.55 -
    Gender, Male/Female
    Units: Participants
        Female
    		 186 188 182 556
        Male
    		 24 25 32 81

    End points

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    End points reporting groups
    Reporting group title
    AIN457 10mg/kg-75mg
    Reporting group description
    		 Participants received AIN457 i.v. (10 mg/kg) at Baseline (BSL), Weeks 2 and 4 then AIN457 75 mg s.c. at Week 8 and injected every 4 weeks

    Reporting group title
    AIN457 10mg/kg-150mg
    Reporting group description
    		 Participants received AIN457 i.v. (10 mg/kg) at BSL, Weeks 2 and 4 then AIN457 150 mg s.c. at Week 8 and injected every 4 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo to AIN457 until week 16 or week 24 based on responder status (>= 20% reduction in tender and swollen joint count). Non-responders were switched to active treatment at week 16. Responders were switched to active treatment at 24 weeks
    Reporting group title
    AIN457 10mg/kg-75mg
    Reporting group description
    		 Participants received AIN457 i.v. (10 mg/kg) at Baseline (BSL), Weeks 2 and 4 then AIN457 75 mg s.c. at Week 8 and injected every 4 weeks up to Week 100, then AIN457 150 mg s.c. starting at week 104

    Reporting group title
    AIN457 10mg/kg-150mg
    Reporting group description
    		 Participants received AIN457 i.v. (10 mg/kg) at BSL, Weeks 2 and 4 then AIN457 150 mg s.c. at Week 8 and injected every 4 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo to AIN457 until week 16 or week 24 based on responder status (>= 20% reduction in tender and swollen joint count). Non-responders were switched to active treatment at week 16. Responders were switched to active treatment at week 24

    Primary: Core Study: Percentage of participants achieving an American College of Rheumatology Response 20 (ACR20) at week 24

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    End point title
    		 Core Study: Percentage of participants achieving an American College of Rheumatology Response 20 (ACR20) at week 24
    End point description
    ACR20 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 20% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient’s assessment of RA pain, patient’s global assessment of disease activity, physician’s global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire [HAQ-DI] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). The ACR20 response results at week 24 used non-responder imputation.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 AIN457 10mg/kg-75mg AIN457 10mg/kg-150mg Placebo
    Number of subjects analysed
    210
    213
    214
    Units: Percentage of Participants
        number (not applicable)
    35.2
    35.2
    19.6
    Statistical analysis title
    		 Percentage of participants ACR20 response
    Comparison groups
    AIN457 10mg/kg-75mg v Placebo
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 3.4
    Statistical analysis title
    		 Percentage of participants ACR20 response
    Comparison groups
    AIN457 10mg/kg-150mg v Placebo
    Number of subjects included in analysis
    427
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 3.4

    Secondary: Change from baseline and week 24 in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI)

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    End point title
    		 Change from baseline and week 24 in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI)
    End point description
    The HAQ-DI assesses a subject's level of functional ability and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities. There are 20 questions in 8 categories of functioning including dressing, rising, eating, walking, hygiene, reach, grip and usual activities. The stem of each item asks 'Over the past week, "are you able to..." perform a particular task'. Each item is scored on a 4 point scale from 0 - 3, representing normal, no difficulty (0), some difficulty (1), much difficulty (2) and unable to do (3). The disability index score is calculated as the mean of the available category scores, ranging from 0 to 3. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 AIN457 10mg/kg-75mg AIN457 10mg/kg-150mg Placebo
    Number of subjects analysed
    171
    188
    71
    Units: Score on a scale
        least squares mean (standard error)
    -0.35 ± 0.039
    -0.35 ± 0.038
    -0.24 ± 0.051
    No statistical analyses for this end point

    Secondary: Change From baseline at week 24 in van der Heijde total modified Sharp score

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    End point title
    		 Change From baseline at week 24 in van der Heijde total modified Sharp score
    End point description
    Separate radiographs of each hand/wrist and each foot were taken at baseline and Week 24. The radiographs were assessed using the van der Heijde modified Sharp score. The change in the Van der Heijde modified Sharp score is calculated against the baseline value
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 AIN457 10mg/kg-75mg AIN457 10mg/kg-150mg Placebo
    Number of subjects analysed
    60
    67
    83
    Units: Score on a scale
        arithmetic mean (standard error)
    0.59 ± 0.62
    0.83 ± 0.68
    1.73 ± 0
    No statistical analyses for this end point

    Secondary: Percentage of patients achieving major clinical response (continuous six-month period of ACR70 response) at week 52

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    End point title
    		 Percentage of patients achieving major clinical response (continuous six-month period of ACR70 response) at week 52
    End point description
    End point type
    Secondary
    End point timeframe
    52 week
    End point values
    		 AIN457 10mg/kg-75mg AIN457 10mg/kg-150mg Placebo
    Number of subjects analysed
    210
    213
    214
    Units: Participants
        number (not applicable)
    2.4
    0.9
    1.4
    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
    18.1
    Reporting groups
    Reporting group title
    Any AIN457 75 mg
    Reporting group description
    		 Participants received AIN457 i.v. (10 mg/kg) at Baseline (BSL), Weeks 2 and 4 then AIN457 75 mg s.c. at Week 8 and injected every 4 weeks or switched from placebo to AIN457 75 mg at week 16 or week 24

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo to AIN457 until week 16 or week 24 based on responder status (>= 20% reduction in tender and swollen joint count). Non-responders were switched to active treatment at week 16. Responders were switched to active treatment

    Reporting group title
    Any AIN457 150 mg
    Reporting group description
    		 Participants received AIN457 i.v. (10 mg/kg) at BSL, Weeks 2 and 4 then AIN457 150 mg s.c. at Week 8 and injected every 4 weeks or switched from placebo to AIN457 75 mg at week 16 or week 24 or was in the extension study (AIN457 150 mg only)

    Serious adverse events
    		 Any AIN457 75 mg Placebo Any AIN457 150 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 301 (10.96%)
    9 / 214 (4.21%)
    48 / 392 (12.24%)
         number of deaths (all causes)
    3
    1
    2
         number of deaths resulting from adverse events
    1
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Femoral artery occlusion
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 301 (0.33%)
    1 / 214 (0.47%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 301 (0.33%)
    1 / 214 (0.47%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 301 (0.66%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Pulmonary oedema
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Anxiety
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Occult blood positive
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Transaminases increased
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Animal bite
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Femur fracture
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         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
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Atrial fibrillation
         subjects affected / exposed
    1 / 301 (0.33%)
    1 / 214 (0.47%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Nervous system disorders
    Carotid artery insufficiency
         subjects affected / exposed
    1 / 301 (0.33%)
    1 / 214 (0.47%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebellar embolism
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral artery embolism
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (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
    Cerebral ischaemia
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (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
    Cerebrovascular insufficiency
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (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
    Encephalomalacia
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Hypoaesthesia
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (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
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Syncope
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Macular degeneration
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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 hernia
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Colitis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    2 / 301 (0.66%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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 and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Acquired claw toe
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Osteoarthritis
         subjects affected / exposed
    1 / 301 (0.33%)
    1 / 214 (0.47%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Osteoporosis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Rheumatoid arthritis
         subjects affected / exposed
    2 / 301 (0.66%)
    1 / 214 (0.47%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 214 (0.47%)
    0 / 392 (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
    Bronchitis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    5 / 392 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Helicobacter gastritis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Herpes zoster
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint tuberculosis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Peritonitis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Pneumonia
         subjects affected / exposed
    4 / 301 (1.33%)
    2 / 214 (0.93%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    Psoas abscess
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Soft tissue infection
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Staphylococcal osteomyelitis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Urosepsis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Hypoglycaemia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 214 (0.00%)
    0 / 392 (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
    Metabolic acidosis
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 214 (0.00%)
    1 / 392 (0.26%)
         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: 2%
    Non-serious adverse events
    		 Any AIN457 75 mg Placebo Any AIN457 150 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    187 / 301 (62.13%)
    94 / 214 (43.93%)
    227 / 392 (57.91%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 301 (5.98%)
    5 / 214 (2.34%)
    12 / 392 (3.06%)
         occurrences all number
    18
    5
    13
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    7 / 301 (2.33%)
    1 / 214 (0.47%)
    8 / 392 (2.04%)
         occurrences all number
    11
    1
    10
    Pyrexia
         subjects affected / exposed
    8 / 301 (2.66%)
    4 / 214 (1.87%)
    13 / 392 (3.32%)
         occurrences all number
    9
    4
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 301 (2.99%)
    4 / 214 (1.87%)
    18 / 392 (4.59%)
         occurrences all number
    9
    4
    23
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 301 (1.00%)
    6 / 214 (2.80%)
    12 / 392 (3.06%)
         occurrences all number
    4
    6
    17
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 301 (2.33%)
    3 / 214 (1.40%)
    10 / 392 (2.55%)
         occurrences all number
    8
    3
    10
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    5 / 301 (1.66%)
    2 / 214 (0.93%)
    10 / 392 (2.55%)
         occurrences all number
    5
    2
    14
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 301 (1.99%)
    3 / 214 (1.40%)
    8 / 392 (2.04%)
         occurrences all number
    6
    3
    9
    Headache
         subjects affected / exposed
    14 / 301 (4.65%)
    10 / 214 (4.67%)
    18 / 392 (4.59%)
         occurrences all number
    19
    10
    20
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 301 (2.99%)
    5 / 214 (2.34%)
    11 / 392 (2.81%)
         occurrences all number
    11
    5
    14
    Lymphopenia
         subjects affected / exposed
    6 / 301 (1.99%)
    4 / 214 (1.87%)
    7 / 392 (1.79%)
         occurrences all number
    8
    6
    7
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 301 (0.66%)
    2 / 214 (0.93%)
    8 / 392 (2.04%)
         occurrences all number
    2
    2
    8
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 301 (1.99%)
    5 / 214 (2.34%)
    13 / 392 (3.32%)
         occurrences all number
    6
    5
    15
    Dental caries
         subjects affected / exposed
    4 / 301 (1.33%)
    1 / 214 (0.47%)
    11 / 392 (2.81%)
         occurrences all number
    4
    1
    15
    Diarrhoea
         subjects affected / exposed
    14 / 301 (4.65%)
    6 / 214 (2.80%)
    22 / 392 (5.61%)
         occurrences all number
    15
    7
    30
    Nausea
         subjects affected / exposed
    6 / 301 (1.99%)
    6 / 214 (2.80%)
    15 / 392 (3.83%)
         occurrences all number
    6
    6
    17
    Dyspepsia
         subjects affected / exposed
    6 / 301 (1.99%)
    1 / 214 (0.47%)
    7 / 392 (1.79%)
         occurrences all number
    6
    1
    7
    Stomatitis
         subjects affected / exposed
    6 / 301 (1.99%)
    1 / 214 (0.47%)
    8 / 392 (2.04%)
         occurrences all number
    9
    1
    12
    Vomiting
         subjects affected / exposed
    4 / 301 (1.33%)
    5 / 214 (2.34%)
    8 / 392 (2.04%)
         occurrences all number
    4
    5
    8
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    6 / 301 (1.99%)
    3 / 214 (1.40%)
    8 / 392 (2.04%)
         occurrences all number
    6
    4
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 301 (6.31%)
    7 / 214 (3.27%)
    16 / 392 (4.08%)
         occurrences all number
    25
    16
    18
    Back pain
         subjects affected / exposed
    6 / 301 (1.99%)
    7 / 214 (3.27%)
    11 / 392 (2.81%)
         occurrences all number
    6
    8
    12
    Muscle spasms
         subjects affected / exposed
    3 / 301 (1.00%)
    4 / 214 (1.87%)
    9 / 392 (2.30%)
         occurrences all number
    4
    4
    10
    Myalgia
         subjects affected / exposed
    5 / 301 (1.66%)
    0 / 214 (0.00%)
    8 / 392 (2.04%)
         occurrences all number
    5
    0
    9
    Rheumatoid arthritis
         subjects affected / exposed
    20 / 301 (6.64%)
    11 / 214 (5.14%)
    17 / 392 (4.34%)
         occurrences all number
    27
    11
    24
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    15 / 301 (4.98%)
    1 / 214 (0.47%)
    31 / 392 (7.91%)
         occurrences all number
    19
    1
    42
    Conjunctivitis
         subjects affected / exposed
    4 / 301 (1.33%)
    0 / 214 (0.00%)
    8 / 392 (2.04%)
         occurrences all number
    4
    0
    8
    Cystitis
         subjects affected / exposed
    4 / 301 (1.33%)
    0 / 214 (0.00%)
    15 / 392 (3.83%)
         occurrences all number
    6
    0
    24
    Gastroenteritis
         subjects affected / exposed
    4 / 301 (1.33%)
    2 / 214 (0.93%)
    13 / 392 (3.32%)
         occurrences all number
    4
    2
    14
    Herpes zoster
         subjects affected / exposed
    8 / 301 (2.66%)
    1 / 214 (0.47%)
    9 / 392 (2.30%)
         occurrences all number
    8
    1
    9
    Influenza
         subjects affected / exposed
    11 / 301 (3.65%)
    2 / 214 (0.93%)
    10 / 392 (2.55%)
         occurrences all number
    11
    2
    10
    Nasopharyngitis
         subjects affected / exposed
    49 / 301 (16.28%)
    14 / 214 (6.54%)
    63 / 392 (16.07%)
         occurrences all number
    70
    16
    110
    Pharyngitis
         subjects affected / exposed
    23 / 301 (7.64%)
    5 / 214 (2.34%)
    18 / 392 (4.59%)
         occurrences all number
    36
    5
    22
    Sinusitis
         subjects affected / exposed
    6 / 301 (1.99%)
    3 / 214 (1.40%)
    8 / 392 (2.04%)
         occurrences all number
    7
    4
    9
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 301 (8.31%)
    10 / 214 (4.67%)
    39 / 392 (9.95%)
         occurrences all number
    34
    11
    58
    Urinary tract infection
         subjects affected / exposed
    28 / 301 (9.30%)
    8 / 214 (3.74%)
    33 / 392 (8.42%)
         occurrences all number
    36
    9
    42
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    6 / 301 (1.99%)
    2 / 214 (0.93%)
    9 / 392 (2.30%)
         occurrences all number
    6
    2
    13

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This study was terminated early by the Sponsor (unrelated to safety) due to the results of study AIN457F2309, which indicated the efficacy of AIN457 was not comparable to the currently available RA treatment
    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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