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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled study of efficacy, safety and tolerability of secukinumab at 12 weeks administered with an i.v. or s.c. loading regimen compared to placebo in patients with active rheumatoid arthritis despite treatment with methotrexate

    Summary
    EudraCT number
    		 2010-024516-34
    Trial protocol
    		 HU   BG   IT   SK  
    Global end of trial date
    30 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    12 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAIN457F2206
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01359943
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Study Director, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Study Director, 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
    30 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate at Week 12 the superior efficacy of secukinumab administered during induction with an i.v. loading regimen or a s.c. loading dose regimen compared to placebo in patients with active RA despite treatment with MTX using the ACR20 criteria. For the primary analysis, the secukinumab regimens were pooled together
    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
    12 Oct 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 50
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Poland: 66
    Country: Number of subjects enrolled
    Slovakia: 42
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    221
    EEA total number of subjects
    199
    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)
    184
    From 65 to 84 years
    37
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were randomized to one of the following 3 treatment groups in a 2:2:1 ratio: secukinumab 10 mg/kg i.v., secukinumab 150 mg s.c. or placebo.

    Period 1
    Period 1 title
    Double-blind (weeks 0 - 16)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 secukinumab 10 mg/kg i.v. loading
    Arm description
    		 secukinumab 10mg/kg i.v. loading at Weeks 0, 2 and 4, and placebo s.c. at weeks 0, 1, 2, 3 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AIN457F
    Other name
    Secukinumab
    Pharmaceutical forms
    Injection
    Routes of administration
    Intracavernous use
    Dosage and administration details
    Secukinumab i.v. (10 mg/kg)

    Arm title
    		 secukinumab 150 mg s.c.
    Arm description
    		 secukinumab 150mg s.c. loading at Weeks 0, 1, 2, 3 and 4, and placebo i.v. at weeks 0, 2 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AINN457F
    Other name
    Secukinumab
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab s.c. 150 mg

    Arm title
    		 placebo
    Arm description
    		 placebo at Weeks 0, 1, 2, 3, 4, 8 & 12, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 16
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    AIN457F
    Other name
    placebo for i.v. infusion
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL 0.9% NaCl solution)

    Number of subjects in period 1
    		secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Started
    88
    89
    44
    Completed
    86
    85
    44
    Not completed
    2
    4
    0
         Consent withdrawn by subject
    -
    2
    -
         Adverse event, non-fatal
    1
    2
    -
         Abnormal laboratory values
    1
    -
    -
    Period 2
    Period 2 title
    Open label 150 mg s.c. (weeks 16 - 52)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 secukinumab 10 mg/kg i.v. loading
    Arm description
    		 secukinumab 10mg/kg i.v. loading at Weeks 0, 2 and 4, and placebo s.c. at weeks 0, 1, 2, 3 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AIN457F
    Other name
    Secukinumab
    Pharmaceutical forms
    Injection
    Routes of administration
    Intracavernous use
    Dosage and administration details
    i.v. (10 mg/kg)

    Arm title
    		 secukinumab 150 mg s.c. loading
    Arm description
    		 secukinumab 150mg s.c. loading at Weeks 0, 1, 2, 3 and 4, and placebo i.v. at weeks 0, 2 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AIN457F
    Other name
    Secukinumab
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    s.c. 150 mg

    Arm title
    		 placebo
    Arm description
    		 placebo at Weeks 0, 1, 2, 3, 4, 8 & 12, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 16
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    AIn457F
    Other name
    Secukinumab placebo
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL 0.9% NaCl solution

    Number of subjects in period 2
    		secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. loading placebo
    Started
    86
    84
    44
    Completed
    78
    71
    36
    Not completed
    8
    13
    8
         Consent withdrawn by subject
    1
    3
    4
         Adverse event, non-fatal
    3
    5
    1
         Protocol deviation
    -
    1
    -
         Administrative problems
    1
    -
    -
         Abnormal laboratory values
    -
    1
    -
         Lack of efficacy
    3
    3
    3
    Period 3
    Period 3 title
    Follow-up (weeks 52 - 60) off treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 secukinumab 10 mg/kg i.v. loading
    Arm description
    		 secukinumab 10mg/kg i.v. loading at Weeks 0, 2 and 4, and placebo s.c. at weeks 0, 1, 2, 3 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8
    Arm type
    		 Experimental

    Investigational medicinal product name
    secukinumab
    Investigational medicinal product code
    AIN457F
    Other name
    Pharmaceutical forms
    Emulsion for injection/infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    10 mg/kg i.v.

    Arm title
    		 secukinumab 150 mg s.c. loading
    Arm description
    		 secukinumab 150mg s.c. loading at Weeks 0, 1, 2, 3 and 4, and placebo i.v. at weeks 0, 2 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8
    Arm type
    		 Experimental

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    AIN457F
    Other name
    Secukinumab
    Pharmaceutical forms
    Suspension and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    150 mg s.c

    Arm title
    		 placebo
    Arm description
    		 placebo at Weeks 0, 1, 2, 3, 4, 8 & 12, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 16
    Arm type
    		 Placebo

    Investigational medicinal product name
    Secukinumab placebo
    Investigational medicinal product code
    AIN457F
    Other name
    Secukinumab placebo
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    100 mL 0.9% NaCl solution

    Number of subjects in period 3
    		secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. loading placebo
    Started
    78
    71
    36
    Completed
    78
    69
    36
    Not completed
    0
    2
    0
         Consent withdrawn by subject
    -
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    secukinumab 10 mg/kg i.v. loading
    Reporting group description
    		 secukinumab 10mg/kg i.v. loading at Weeks 0, 2 and 4, and placebo s.c. at weeks 0, 1, 2, 3 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8

    Reporting group title
    secukinumab 150 mg s.c.
    Reporting group description
    		 secukinumab 150mg s.c. loading at Weeks 0, 1, 2, 3 and 4, and placebo i.v. at weeks 0, 2 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8

    Reporting group title
    placebo
    Reporting group description
    		 placebo at Weeks 0, 1, 2, 3, 4, 8 & 12, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 16

    Reporting group values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo Total
    Number of subjects
    		 88 89 44 221
    Age categorical
    Units: Subjects
        Adults (≥18-<65 years)
    		 73 71 40 184
        From ≥65-<75 years
    		 13 17 4 34
        ≥75 years
    		 2 1 0 3
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 53.8 ( 11.81 ) 54.5 ( 12.26 ) 53.5 ( 9.33 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 67 72 37 176
        Male
    		 21 17 7 45

    End points

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    End points reporting groups
    Reporting group title
    secukinumab 10 mg/kg i.v. loading
    Reporting group description
    		 secukinumab 10mg/kg i.v. loading at Weeks 0, 2 and 4, and placebo s.c. at weeks 0, 1, 2, 3 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8

    Reporting group title
    secukinumab 150 mg s.c.
    Reporting group description
    		 secukinumab 150mg s.c. loading at Weeks 0, 1, 2, 3 and 4, and placebo i.v. at weeks 0, 2 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8

    Reporting group title
    placebo
    Reporting group description
    		 placebo at Weeks 0, 1, 2, 3, 4, 8 & 12, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 16
    Reporting group title
    secukinumab 10 mg/kg i.v. loading
    Reporting group description
    		 secukinumab 10mg/kg i.v. loading at Weeks 0, 2 and 4, and placebo s.c. at weeks 0, 1, 2, 3 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8

    Reporting group title
    secukinumab 150 mg s.c. loading
    Reporting group description
    		 secukinumab 150mg s.c. loading at Weeks 0, 1, 2, 3 and 4, and placebo i.v. at weeks 0, 2 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8

    Reporting group title
    placebo
    Reporting group description
    		 placebo at Weeks 0, 1, 2, 3, 4, 8 & 12, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 16
    Reporting group title
    secukinumab 10 mg/kg i.v. loading
    Reporting group description
    		 secukinumab 10mg/kg i.v. loading at Weeks 0, 2 and 4, and placebo s.c. at weeks 0, 1, 2, 3 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8

    Reporting group title
    secukinumab 150 mg s.c. loading
    Reporting group description
    		 secukinumab 150mg s.c. loading at Weeks 0, 1, 2, 3 and 4, and placebo i.v. at weeks 0, 2 and 4, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 8

    Reporting group title
    placebo
    Reporting group description
    		 placebo at Weeks 0, 1, 2, 3, 4, 8 & 12, followed by secukinumab 150mg s.c. every 4 weeks starting at Week 16

    Primary: Percentage of participants who achieve American College of Rheumatology Response of 20 (ACR20)

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    End point title
    		 Percentage of participants who achieve American College of Rheumatology Response of 20 (ACR20)
    End point description
    A participant was considered to be a responder according to the ACR20 criteria if the participant had at least 20% improvement in both the tender joint count and swollen joint count measures, and in at least 3 of the following 5 measures: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, Health Assessment Questionnaire (HAQ©) score, and/or C-reactive protein (CRP)/Erythrocyte Sedimentation Rate (ESR).
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    88
    89
    44
    Units: Percentage of participants
        number (not applicable)
    53.4
    44.9
    40.9
    Statistical analysis title
    		 To demonstrate secukinimab superiority at Week 12
    Statistical analysis description
    primary objective was to demonstrate at Week 12 the superior efficacy ofsecukinumab administered during induction with an i.v. loading regimen or a s.c. loading dose regimencompared to placebo in patients with active RA despite treatment with MTX using the ACR20 criteria.For the primary analysis, the secukinumab regimens were pooled together.
    Comparison groups
    secukinumab 10 mg/kg i.v. loading v secukinumab 150 mg s.c. v placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3559
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: Percentage of participants who achieve ACR50 and ACR70

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    End point title
    		 Percentage of participants who achieve ACR50 and ACR70
    End point description
    A participant was considered to be a responder according to the ACR50 or ACR70 criteria if the participant had at least 50% or 70% improvement, respectively, in both the tender joint count and swollen joint count measures, and in at least 3 of the following 5 measures: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, Health Assessment Questionnaire (HAQ©) score, and/or C-reactive protein (CRP)/Erythrocyte Sedimentation Rate (ESR).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    88
    89
    44
    Units: Percentage of participants
    number (not applicable)
        ACR50
    20.5
    18
    11.4
        ACR70
    8
    5.6
    0
    No statistical analyses for this end point

    Secondary: Change from baseline in Health Assessment Questionnaire-Disease Index (HAQ-DI) score.

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    End point title
    		 Change from baseline in Health Assessment Questionnaire-Disease Index (HAQ-DI) score.
    End point description
    The HAQ measures physical disability and functional status. It has 4 dimensions: disability, pain, drug side effects and dollar costs. In this trial, only the disability dimension was used. The disability dimension consists of 20 multiple choice items concerning difficulty in performing 8 common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and activities. Participants choose from four response categories: 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty) and 3 (unable to do). Within each of the 8 categories, only the item indicating the most severe impairment contributes to the category score. The HAQ score is calculated by summing the computed scores for each category and dividing by the number of categories answered. It ranges from 0 (without any difficulty) to 3 (unable to do). A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 12 Weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    88
    89
    44
    Units: score on a scale
        least squares mean (standard error)
    -0.35 ( 0.052 )
    -0.28 ( 0.053 )
    -0.17 ( 0.074 )
    No statistical analyses for this end point

    Secondary: Change from baseline in DAS28 using high sensitivity C-reactive protein (hsCRP) (DAS28-CRP)

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    End point title
    		 Change from baseline in DAS28 using high sensitivity C-reactive protein (hsCRP) (DAS28-CRP)
    End point description
    The Disease Activity Score (DAS) is a combined index to measure disease activity in RA participants. DAS28-CRP is determined using the following variables: 28-joint counts (tender28 and swollen28), CRP, and the participant's general health (GH) or global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm (0 = and 100 = ). Using the data from these variables, DAS28-CRP is calculated using the following formula: DAS28-4(crp) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96. The calculation results in a DAS28-CRP score from 0 to 10 indicating the current activity of the rheumatoid arthritis of your patient. A DAS28 above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity. Remission is achieved by a DAS28 lower than 2.6. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    85
    82
    43
    Units: score on a scale
        least squares mean (standard error)
    -1.67 ( 0.119 )
    -1.65 ( 0.12 )
    -1.21 ( 0.166 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Disease Activity Score 28 response using ESR (DAS28-ESR)

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    End point title
    		 Change from baseline in Disease Activity Score 28 response using ESR (DAS28-ESR)
    End point description
    The Disease Activity Score (DAS) is a combined index to measure disease activity in RA participants. DAS28 is determined using the following variables: 28-joint counts (tender28 and swollen28), erythrocyte sedimentation rate (ESR), and the participant's general health (GH) or global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm (0 = and 100 = ). Using the data from these variables, DAS28-ESR is calculated using the following formula: DAS28 = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.70 * ln(ESR) + 0.014 * GH. The calculation results in a DAS28-ESR score from 0 to 10 indicating the current activity of the rheumatoid arthritis of your patient. A DAS28 above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity. Remission is achieved by a DAS28 lower than 2.6. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    84
    82
    43
    Units: score on a scale
        least squares mean (standard error)
    -1.98 ( 0.126 )
    -1.8 ( 0.128 )
    -1.46 ( 0.179 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with European League Against Rheumatism (EULAR) response

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    End point title
    		 Percentage of participants with European League Against Rheumatism (EULAR) response
    End point description
    EULAR response criteria are based on DAS28 status in combination with DAS28 improvements. The EULAR response criteria are as follows: present DAS28 <3.2 with DAS28 improvement >1.2 corresponds to 'good response'; present DAS28 <3.2 with DAS28 improvement between 0.6 to 1.2, or present DAS28 between 3.2 to 5.1 with DAS28 improvement from 0.6 to >1.2, or present DAS28 >5.2 with DAS28 improvement >1.2 correspond to 'moderate response; present DAS28 <3.2 with DAS28 improvement <0.6, or present DAS28 between 3.2 to 5.1 with DAS28 improvement <0.6, or present DAS28 >5.1 with DAS28 improvement <0.6 to 1.2 correspond to 'no response'.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    88
    89
    44
    Units: Percentage of participants
    number (not applicable)
        Good response
    28.4
    27
    13.6
        Moderate response
    46.6
    44.9
    52.3
        No response
    25
    28.1
    34.1
    No statistical analyses for this end point

    Secondary: Change from baseline in swollen 66-joint count

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    End point title
    		 Change from baseline in swollen 66-joint count
    End point description
    The 66 joints assessed for swelling included the 8 distal interphalangeal, 10 proximal interphalangeal and 10 metacarpophalangeal joints of the hands, the 10 metatarsophalangeal and 10 proximal interphalangeal joints of the feet, the 2 wrists, 2 elbows , 2 shoulders , 2 acromioclavicular, 2 sternoclavicular, 2 temporomandibular, 2 knee, 2 talo-tibial, and 2 mid-tarsal joints. Swelling was graded present (1) or absent (0). A negative change in baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    88
    89
    44
    Units: Number of joints
        least squares mean (standard error)
    -9.49 ( 0.607 )
    -9.81 ( 0.612 )
    -7.88 ( 0.863 )
    No statistical analyses for this end point

    Secondary: Change from baseline in tender 68-joint count

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    End point title
    		 Change from baseline in tender 68-joint count
    End point description
    The 68 joints assessed for tenderness included the 8 distal interphalangeal, 10 proximal interphalangeal and 10 metacarpophalangeal joints of the hands, the 10 metatarsophalangeal and 10 proximal interphalangeal joints of the feet, the 2 wrists, 2 elbows , 2 shoulders , 2 acromioclavicular, 2 sternoclavicular, 2 temporomandibular, 2 hip, 2 knee, 2 talo-tibial, and 2 mid-tarsal joints. Joint tenderness was graded present (1) or absent (0). A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    88
    89
    44
    Units: Number of joints
        least squares mean (standard error)
    -10.31 ( 1.093 )
    -11.99 ( 1.099 )
    -9.5 ( 1.549 )
    No statistical analyses for this end point

    Secondary: Change from baseline in participant's assessment of rheumatoid arthritis (RA) pain

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    End point title
    		 Change from baseline in participant's assessment of rheumatoid arthritis (RA) pain
    End point description
    The patient’s assessment of pain was performed using 100 mm visual analog scale (VAS) ranging from 0 (no pain) to 100 (unbearable pain) after the question “Please indicate with a vertical mark through the horizontal line the most pain you had from your rheumatoid arthritis over the last 24 hours”. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    88
    89
    44
    Units: score on a scale
        least squares mean (standard error)
    -14.41 ( 2.057 )
    -12.6 ( 2.071 )
    -6.66 ( 2.902 )
    No statistical analyses for this end point

    Secondary: Change from baseline in participant's global assessment of disease activity

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    End point title
    		 Change from baseline in participant's global assessment of disease activity
    End point description
    The patient’s global assessment of disease activity was performed using 100 mm VAS ranging from 0 (very good) to 100 (very poor), after the question "Considering all the ways rheumatoid arthritis affects you, please indicate with a vertical mark through the horizontal line how well you are doing today”. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    88
    89
    44
    Units: score on a scale
        least squares mean (standard error)
    -18.58 ( 2.042 )
    -15.29 ( 2.063 )
    -9.93 ( 2.884 )
    No statistical analyses for this end point

    Secondary: Change from baseline in physician's global assessment of disease activity

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    End point title
    		 Change from baseline in physician's global assessment of disease activity
    End point description
    The physician’s global assessment of disease activity was performed using 100 mm VAS ranging from 0 (very good) to 100 (very poor), after the question “Considering all the ways rheumatoid arthritis affects your patient, how would you rate his or her current condition?”. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    88
    89
    44
    Units: score on a scale
        least squares mean (standard error)
    -27.05 ( 1.925 )
    -29.01 ( 1.95 )
    18.88 ( 2.726 )
    No statistical analyses for this end point

    Secondary: Change from baseline in hsCRP

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    End point title
    		 Change from baseline in hsCRP
    End point description
    Blood for this assessment was obtained to identify the presence of inflammation, to determine its severity, and to monitor response to treatment. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    88
    89
    44
    Units: mg/L
        least squares mean (standard error)
    -6 ( 0.938 )
    -5.72 ( 0.946 )
    -1.69 ( 1.336 )
    No statistical analyses for this end point

    Secondary: Change from baseline in ESR

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    End point title
    		 Change from baseline in ESR
    End point description
    Blood for this assessment was obtained to monitor disease activity and response to therapy. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks
    End point values
    		 secukinumab 10 mg/kg i.v. loading secukinumab 150 mg s.c. placebo
    Number of subjects analysed
    88
    89
    44
    Units: mm/hr
        least squares mean (standard error)
    -16.68 ( 1.409 )
    -12.43 ( 1.425 )
    -10.53 ( 1.993 )
    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
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Up to Week 16 - AIN457 150 mg sc load
    Reporting group description
    		 Up to Week 16 - AIN457 150 mg sc load

    Reporting group title
    Up to Week 16 - AIN457 10 mg/kg - 150mg
    Reporting group description
    		 Up to Week 16 - AIN457 10 mg/kg - 150mg

    Reporting group title
    From Week 16 through Week 52 - AIN457 150 mg sc open label
    Reporting group description
    		 From Week 16 through Week 52 - AIN457 150 mg sc open label

    Reporting group title
    Follow-up period - AIN457 150 mg sc open label
    Reporting group description
    		 Follow-up period - AIN457 150 mg sc open label

    Reporting group title
    Up to Week 16 - Placebo
    Reporting group description
    		 Up to Week 16 - Placebo

    Serious adverse events
    		 Up to Week 16 - AIN457 150 mg sc load Up to Week 16 - AIN457 10 mg/kg - 150mg From Week 16 through Week 52 - AIN457 150 mg sc open label Follow-up period - AIN457 150 mg sc open label Up to Week 16 - Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 89 (3.37%)
    2 / 88 (2.27%)
    18 / 214 (8.41%)
    3 / 214 (1.40%)
    1 / 44 (2.27%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal adenoma
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    1 / 214 (0.47%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    1 / 214 (0.47%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    1 / 214 (0.47%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid lung
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Arteriogram coronary
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    2 / 214 (0.93%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Up to Week 16 - AIN457 150 mg sc load Up to Week 16 - AIN457 10 mg/kg - 150mg From Week 16 through Week 52 - AIN457 150 mg sc open label Follow-up period - AIN457 150 mg sc open label Up to Week 16 - Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 89 (33.71%)
    17 / 88 (19.32%)
    78 / 214 (36.45%)
    10 / 214 (4.67%)
    18 / 44 (40.91%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 88 (1.14%)
    11 / 214 (5.14%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    2
    1
    11
    0
    1
    Varicose vein
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    1
    Immune system disorders
    Immunodeficiency
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    0
    0
    1
    Cough
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    7 / 214 (3.27%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    8
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 88 (2.27%)
    3 / 214 (1.40%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    2
    3
    0
    0
    Pharyngeal erythema
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    1
    Mood altered
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    1
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    1
    0
    1
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 89 (4.49%)
    2 / 88 (2.27%)
    5 / 214 (2.34%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    4
    2
    5
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 88 (2.27%)
    2 / 214 (0.93%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Leukopenia
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 88 (1.14%)
    5 / 214 (2.34%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    1
    5
    0
    0
    Dyspepsia
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 88 (1.14%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 89 (1.12%)
    2 / 88 (2.27%)
    2 / 214 (0.93%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    3
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    1
    0
    0
    0
    2
    Rash
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 88 (1.14%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    3 / 214 (1.40%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    1
    0
    4
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    2 / 214 (0.93%)
    1 / 44 (2.27%)
         occurrences all number
    1
    0
    1
    2
    1
    Fibromyalgia
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Rheumatoid arthritis
         subjects affected / exposed
    5 / 89 (5.62%)
    0 / 88 (0.00%)
    12 / 214 (5.61%)
    5 / 214 (2.34%)
    2 / 44 (4.55%)
         occurrences all number
    6
    0
    12
    5
    2
    Spinal pain
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 88 (1.14%)
    5 / 214 (2.34%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    5
    0
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 88 (0.00%)
    2 / 214 (0.93%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    4
    0
    0
    Erythema migrans
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    2
    Gastroenteritis
         subjects affected / exposed
    1 / 89 (1.12%)
    2 / 88 (2.27%)
    3 / 214 (1.40%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    1
    2
    3
    0
    1
    Influenza
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    4 / 214 (1.87%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    2
    0
    5
    0
    1
    Laryngitis
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 88 (1.14%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 89 (5.62%)
    5 / 88 (5.68%)
    11 / 214 (5.14%)
    1 / 214 (0.47%)
    4 / 44 (9.09%)
         occurrences all number
    5
    5
    14
    1
    5
    Pharyngitis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    6 / 214 (2.80%)
    1 / 214 (0.47%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    7
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    5 / 214 (2.34%)
    0 / 214 (0.00%)
    3 / 44 (6.82%)
         occurrences all number
    1
    0
    5
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 88 (1.14%)
    17 / 214 (7.94%)
    1 / 214 (0.47%)
    0 / 44 (0.00%)
         occurrences all number
    1
    1
    19
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 88 (2.27%)
    3 / 214 (1.40%)
    0 / 214 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    2
    3
    0
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 88 (0.00%)
    3 / 214 (1.40%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    2
    0
    3
    0
    1
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
    1 / 214 (0.47%)
    0 / 214 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    1
    0
    1
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 88 (0.00%)
    0 / 214 (0.00%)
    0 / 214 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    1

    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.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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