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    Clinical Trial Results:
    A Phase 2, Open-Label, Non-Comparative, Multi-Center Extension Study to Evaluate the Long-term Safety and Efficacy of ASP015K in Subjects Previously Enrolled in a Phase 2 ASP015K Rheumatoid Arthritis Study

    Summary
    EudraCT number
    2011-006021-23
    Trial protocol
    HU   BE   CZ   BG   PL  
    Global end of trial date
    25 Mar 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Mar 2017
    First version publication date
    09 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    015K-CL-RA25
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01711814
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc. (APGD)
    Sponsor organisation address
    1 Astellas Way, Northbrook , IL, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc. (APGD), Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc. (APGD), Astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this phase 2 extension study was to evaluate the long-term safety and efficacy of ASP015K in patients with rheumatoid arthritis (RA) who had completed one of two 12-week double-blind, placebo-controlled phase 2b studies: Study 015K-CL-RA21 (wherein patients received ASP015K or placebo plus a weekly dose of 7.5 to 25 mg of methotrexate (MTX)) or Study 015K-CL-RA22 (wherein patients received ASP015K or placebo).
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Sep 2012
    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
    United States: 256
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Bulgaria: 20
    Country: Number of subjects enrolled
    Czech Republic: 52
    Country: Number of subjects enrolled
    Hungary: 40
    Country: Number of subjects enrolled
    Poland: 138
    Country: Number of subjects enrolled
    Colombia: 23
    Country: Number of subjects enrolled
    Mexico: 74
    Worldwide total number of subjects
    611
    EEA total number of subjects
    258
    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)
    508
    From 65 to 84 years
    102
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    This extension study was conducted at 51 contracted sites in a total of 8 countries in 3 geographic regions: North America (United States 20 sites), Europe (Belgium 2 sites, Bulgaria 3 sites, Czech Republic 4 sites, Hungary 6 sites, Poland 7 sites) and Latin America (Colombia 5 sites, Mexico 4 sites).

    Pre-assignment
    Screening details
    Participants in this extension study 015k-CL-RA25 (shortened to RA25 for ease of reading) rolled over from either 015K-CL-RA21 (shortened to RA21 for ease of reading) or 015K-CL-RA22 (shortened to RA22 for ease of reading). Baseline of RA25 was the last procedure in RA21/RA22 prior to dosing (Visit day 1) of RA25.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    This was an open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    RA21/RA22 Placebo
    Arm description
    Participants who received placebo in studies RA21 or RA22 received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ASP015K
    Investigational medicinal product code
    ASP015K
    Other name
    Peficitinib (USAN)
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received open-label ASP015K 100 mg daily. Study drug should have been taken as close to the same time each day as possible. Study drug was to be administered orally with approximately 240 mL (8 oz.) of water, and must have been taken with food.

    Arm title
    RA21/RA22 ASP015K 25 mg
    Arm description
    Participants who previously completed RA21 or RA22 study and received ASP015K 25 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ASP015K
    Investigational medicinal product code
    ASP015K
    Other name
    Peficitinib (USAN)
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received open-label ASP015K 100 mg daily. Study drug should have been taken as close to the same time each day as possible. Study drug was to be administered orally with approximately 240 mL (8 oz.) of water, and must have been taken with food.

    Arm title
    RA21/RA22 ASP015K 50 mg
    Arm description
    Participants who previously completed RA21 or RA22 study and received ASP015K 50 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ASP015K
    Investigational medicinal product code
    ASP015K
    Other name
    Peficitinib (USAN)
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received open-label ASP015K 100 mg daily. Study drug should have been taken as close to the same time each day as possible. Study drug was to be administered orally with approximately 240 mL (8 oz.) of water, and must have been taken with food.

    Arm title
    RA21/RA22 ASP015K 100 mg
    Arm description
    Participants who previously completed RA21 or RA22 study and received ASP015K 100 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ASP015K
    Investigational medicinal product code
    ASP015K
    Other name
    Peficitinib (USAN)
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received open-label ASP015K 100 mg daily. Study drug should have been taken as close to the same time each day as possible. Study drug was to be administered orally with approximately 240 mL (8 oz.) of water, and must have been taken with food.

    Arm title
    RA21/RA22 ASP015K 150 mg
    Arm description
    Participants who previously completed RA21 or RA22 study and received ASP015K 150 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ASP015K
    Investigational medicinal product code
    ASP015K
    Other name
    Peficitinib (USAN)
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received open-label ASP015K 100 mg daily. Study drug should have been taken as close to the same time each day as possible. Study drug was to be administered orally with approximately 240 mL (8 oz.) of water, and must have been taken with food.

    Number of subjects in period 1
    RA21/RA22 Placebo RA21/RA22 ASP015K 25 mg RA21/RA22 ASP015K 50 mg RA21/RA22 ASP015K 100 mg RA21/RA22 ASP015K 150 mg
    Started
    116
    112
    124
    128
    131
    Completed
    66
    60
    61
    67
    65
    Not completed
    50
    52
    63
    61
    66
         Death
    -
    -
    -
    1
    1
         Met discontinuation criteria
    8
    10
    14
    13
    17
         Miscellaneous
    -
    -
    1
    -
    1
         Protocol violation
    -
    -
    -
    1
    -
         Adverse event
    9
    10
    6
    12
    4
         Lack of efficacy
    5
    4
    8
    9
    6
         Did not meet ACR20 response by week 13
    6
    5
    5
    4
    9
         Withdrawal by participant
    16
    16
    25
    18
    21
         Site closure
    2
    5
    1
    2
    4
         Lost to follow-up
    4
    2
    3
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RA21/RA22 Placebo
    Reporting group description
    Participants who received placebo in studies RA21 or RA22 received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 25 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 25 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 50 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 50 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 100 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 100 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 150 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 150 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group values
    RA21/RA22 Placebo RA21/RA22 ASP015K 25 mg RA21/RA22 ASP015K 50 mg RA21/RA22 ASP015K 100 mg RA21/RA22 ASP015K 150 mg Total
    Number of subjects
    116 112 124 128 131
    Age categorical
    Units: Subjects
    Age continuous
    Age values were based on all enrolled participants.
    Units: years
        arithmetic mean (standard deviation)
    52.4 ± 12.14 52.2 ± 11.48 53.3 ± 11.53 54.5 ± 12.05 54.2 ± 12.39 -
    Gender categorical
    Gender values were based on all enrolled participants.
    Units:
        Male
    17 19 22 22 27 107
        Female
    99 93 102 106 104 504
    Subject analysis sets

    Subject analysis set title
    Total RA25
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All participants who enrolled in the RA25 extension study. Participants received open-label ASP015K 100 mg daily for up to 104 weeks.

    Subject analysis sets values
    Total RA25
    Number of subjects
    611
    Age categorical
    Units: Subjects
    Age continuous
    Age values were based on all enrolled participants.
    Units: years
        arithmetic mean (standard deviation)
    53.4 ± 11.93
    Gender categorical
    Gender values were based on all enrolled participants.
    Units:
        Male
    107
        Female
    504

    End points

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    End points reporting groups
    Reporting group title
    RA21/RA22 Placebo
    Reporting group description
    Participants who received placebo in studies RA21 or RA22 received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 25 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 25 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 50 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 50 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 100 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 100 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 150 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 150 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Subject analysis set title
    Total RA25
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All participants who enrolled in the RA25 extension study. Participants received open-label ASP015K 100 mg daily for up to 104 weeks.

    Primary: Number of Participants with Adverse Events (AEs)

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    End point title
    Number of Participants with Adverse Events (AEs) [1]
    End point description
    Analysis population consisted of the Safety Analysis Set (SAF). SAF was defined as all participants who were enrolled & received at least 1 dose of study drug. AE is defined as any untoward medical occurrence in a participant administered a study drug or has undergone study procedures & which does not necessarily have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) was defined as an AE that started or worsened in severity after first dose of study drug in RA25, excluding events continuing from the preceding study (RA21 or RA22). AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.03, where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening & Grade 5 = Death related to AE. A drug-related TEAE was defined as any TEAE with at least a possible relationship to study treatment as assessed by the investigator or with missing assessment of the causal relationship.
    End point type
    Primary
    End point timeframe
    Up to 104 weeks. Date of last evaluation was 25 Mar 2016.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses applicable for this end point.
    End point values
    RA21/RA22 Placebo RA21/RA22 ASP015K 25 mg RA21/RA22 ASP015K 50 mg RA21/RA22 ASP015K 100 mg RA21/RA22 ASP015K 150 mg Total RA25
    Number of subjects analysed
    116
    112
    124
    128
    131
    611
    Units: Participants
        TEAE
    80
    85
    98
    101
    99
    463
        Drug-related TEAE
    39
    38
    49
    47
    49
    222
        Death
    0
    0
    0
    1
    1
    2
        Serious Adverse Event (SAE)
    14
    11
    14
    25
    16
    80
        Drug-related SAE
    5
    6
    5
    5
    3
    24
        TEAE ≥ Grade 3 in severity
    13
    10
    15
    23
    17
    78
        TEAE leading to permanent discontinuation
    9
    9
    8
    11
    6
    43
        Drug-related TEAE leading to permanent disc.
    8
    7
    5
    3
    4
    27
        SAE leading to permanent discontinuation
    2
    1
    3
    5
    2
    13
        Drug-related SAE leading to permanent disc.
    2
    1
    3
    1
    1
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 104 weeks. Date of last evaluation was 25 Mar 2016.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    RA21/RA22 Placebo
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received placebo, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 25 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 25 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 50 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 50 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 100 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 100 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    RA21/RA22 ASP015K 150 mg
    Reporting group description
    Participants who previously completed RA21 or RA22 study and received ASP015K 150 mg, received open-label ASP015K 100 mg daily in this RA25 extension study for up to 104 weeks.

    Reporting group title
    Total RA25
    Reporting group description
    All participants who enrolled in the RA25 extension study. Participants received open-label ASP015K 100 mg daily for up to 104 weeks.

    Serious adverse events
    RA21/RA22 Placebo RA21/RA22 ASP015K 25 mg RA21/RA22 ASP015K 50 mg RA21/RA22 ASP015K 100 mg RA21/RA22 ASP015K 150 mg Total RA25
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 116 (12.07%)
    11 / 112 (9.82%)
    14 / 124 (11.29%)
    25 / 128 (19.53%)
    16 / 131 (12.21%)
    80 / 611 (13.09%)
         number of deaths (all causes)
    0
    0
    0
    1
    1
    2
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthrodesis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Liposuction
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign salivary gland neoplasm
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leiomyoma
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    1 / 131 (0.76%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Perforated ulcer
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pseudocyst
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Reproductive system and breast disorders
    Dysfunctional uterine bleeding
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    2 / 131 (1.53%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Operative haemorrhage
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Spinal compression fracture
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    1 / 131 (0.76%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    2 / 128 (1.56%)
    0 / 131 (0.00%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Headache
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal sphincter insufficiency
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    1 / 124 (0.81%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 1
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand deformity
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    1 / 128 (0.78%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    3 / 124 (2.42%)
    2 / 128 (1.56%)
    0 / 131 (0.00%)
    6 / 611 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 2
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster ophthalmic
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 112 (0.89%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    1 / 124 (0.81%)
    0 / 128 (0.00%)
    0 / 131 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    3 / 128 (2.34%)
    0 / 131 (0.00%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 112 (0.00%)
    0 / 124 (0.00%)
    0 / 128 (0.00%)
    1 / 131 (0.76%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    RA21/RA22 Placebo RA21/RA22 ASP015K 25 mg RA21/RA22 ASP015K 50 mg RA21/RA22 ASP015K 100 mg RA21/RA22 ASP015K 150 mg Total RA25
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 116 (50.86%)
    54 / 112 (48.21%)
    70 / 124 (56.45%)
    69 / 128 (53.91%)
    58 / 131 (44.27%)
    310 / 611 (50.74%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 116 (2.59%)
    4 / 112 (3.57%)
    7 / 124 (5.65%)
    5 / 128 (3.91%)
    7 / 131 (5.34%)
    26 / 611 (4.26%)
         occurrences all number
    3
    4
    7
    6
    7
    27
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    9 / 116 (7.76%)
    4 / 112 (3.57%)
    4 / 124 (3.23%)
    4 / 128 (3.13%)
    7 / 131 (5.34%)
    28 / 611 (4.58%)
         occurrences all number
    10
    8
    4
    5
    8
    35
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 116 (2.59%)
    2 / 112 (1.79%)
    2 / 124 (1.61%)
    9 / 128 (7.03%)
    2 / 131 (1.53%)
    18 / 611 (2.95%)
         occurrences all number
    3
    3
    2
    10
    2
    20
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 116 (5.17%)
    5 / 112 (4.46%)
    6 / 124 (4.84%)
    12 / 128 (9.38%)
    3 / 131 (2.29%)
    32 / 611 (5.24%)
         occurrences all number
    7
    5
    7
    13
    3
    35
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 116 (6.03%)
    3 / 112 (2.68%)
    7 / 124 (5.65%)
    7 / 128 (5.47%)
    3 / 131 (2.29%)
    27 / 611 (4.42%)
         occurrences all number
    10
    4
    7
    15
    4
    40
    Nausea
         subjects affected / exposed
    8 / 116 (6.90%)
    2 / 112 (1.79%)
    5 / 124 (4.03%)
    8 / 128 (6.25%)
    2 / 131 (1.53%)
    25 / 611 (4.09%)
         occurrences all number
    10
    2
    5
    9
    2
    28
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    6 / 116 (5.17%)
    4 / 112 (3.57%)
    6 / 124 (4.84%)
    5 / 128 (3.91%)
    3 / 131 (2.29%)
    24 / 611 (3.93%)
         occurrences all number
    6
    4
    9
    6
    3
    28
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    5 / 116 (4.31%)
    8 / 112 (7.14%)
    11 / 124 (8.87%)
    5 / 128 (3.91%)
    9 / 131 (6.87%)
    38 / 611 (6.22%)
         occurrences all number
    6
    9
    11
    6
    10
    42
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    12 / 116 (10.34%)
    10 / 112 (8.93%)
    12 / 124 (9.68%)
    3 / 128 (2.34%)
    5 / 131 (3.82%)
    42 / 611 (6.87%)
         occurrences all number
    17
    12
    14
    3
    6
    52
    Influenza
         subjects affected / exposed
    3 / 116 (2.59%)
    3 / 112 (2.68%)
    6 / 124 (4.84%)
    10 / 128 (7.81%)
    5 / 131 (3.82%)
    27 / 611 (4.42%)
         occurrences all number
    3
    4
    10
    10
    5
    32
    Nasopharyngitis
         subjects affected / exposed
    7 / 116 (6.03%)
    9 / 112 (8.04%)
    12 / 124 (9.68%)
    10 / 128 (7.81%)
    4 / 131 (3.05%)
    42 / 611 (6.87%)
         occurrences all number
    7
    11
    16
    16
    6
    56
    Pharyngitis
         subjects affected / exposed
    1 / 116 (0.86%)
    6 / 112 (5.36%)
    4 / 124 (3.23%)
    7 / 128 (5.47%)
    3 / 131 (2.29%)
    21 / 611 (3.44%)
         occurrences all number
    1
    6
    4
    9
    4
    24
    Sinusitis
         subjects affected / exposed
    4 / 116 (3.45%)
    3 / 112 (2.68%)
    2 / 124 (1.61%)
    4 / 128 (3.13%)
    7 / 131 (5.34%)
    20 / 611 (3.27%)
         occurrences all number
    6
    4
    2
    4
    7
    23
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 116 (16.38%)
    9 / 112 (8.04%)
    15 / 124 (12.10%)
    17 / 128 (13.28%)
    17 / 131 (12.98%)
    77 / 611 (12.60%)
         occurrences all number
    24
    12
    21
    21
    20
    98
    Urinary tract infection
         subjects affected / exposed
    14 / 116 (12.07%)
    9 / 112 (8.04%)
    8 / 124 (6.45%)
    15 / 128 (11.72%)
    6 / 131 (4.58%)
    52 / 611 (8.51%)
         occurrences all number
    19
    13
    8
    20
    9
    69
    Urinary tract infection bacterial
         subjects affected / exposed
    5 / 116 (4.31%)
    5 / 112 (4.46%)
    3 / 124 (2.42%)
    7 / 128 (5.47%)
    8 / 131 (6.11%)
    28 / 611 (4.58%)
         occurrences all number
    5
    7
    4
    8
    9
    33

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2012
    ● Dosing instructions revised to state “take with food” ● Safety follow-up period extended to 30 days ● Clarified inclusion criterion regarding eligibility for women of child-bearing potential ● Clarified discontinuation criterion for symptomatic CPK elevation ● Corrected the description of study drug packaging and labeling ● Other clarifications and administrative changes made. These changes to the protocol were included prior to the enrollment of any patients in RA25.
    22 Jun 2012
    ● Updated planned study period in accordance with revised timelines ● Updated planned number of patients ● Provided clearly defined laboratory exclusion criteria ● Included changes in allowed and prohibited concomitant medications ● Clarified definition of efficacy end points and efficacy data to be summarized ● Clarified dosing instructions and requirements for dose reduction ● Corrected instructions for performing joint assessments ● Added requirement for estimated glomerular filtration rate (eGFR) calculation by central laboratory at all visits ● Other clarifications and administrative changes made. These changes to the protocol were included prior to the enrollment of any patients in RA25.
    15 Aug 2012
    ● Updated planned study period to reflect more accurate timelines per regulatory feedback ● Added IEC to approval required for Informed Consent ● Revised inclusion criteria to specify completion of phase 2 study and included the time period allowed to roll over into the extension study ● Clarified exclusion criteria such that patients who discontinue study drug prior to week 12 visit in phase 2 study will not be eligible ● Updated Schedule of Assessments and statistical methods ● Updated allowed doses of oral morphine ● Clarified timepoints when Disease Activity Score (DAS) in 28 joints (DAS28) is performed ● Updated blood volumes collected during first and second years of study ● Other clarifications and administrative changes made. These changes to the protocol were included prior to the enrollment of any patients in RA25.
    02 Apr 2013
    ● Revised inclusion criteria regarding use of contraceptives, and limitations on ova donation for women of child-bearing potential and sperm donation for men ● Added inclusion criteria that patients agree not to participate in another interventional trial while on treatment in RA25 ● Clarified that waivers to inclusion and exclusion criteria would not be allowed ● Added exclusion criteria for patients with significant lymphopenia and discontinuation criteria to mandate patients discontinue study drug in presence of severe lymphopenia ● Revised exclusion criteria for laboratory values to be consistent with discontinuation laboratory criteria for RA21 and RA22 ● Modified criteria for continuing study treatment from “requiring achievement of an American College of Rheumatology response (ACR20) by week 13” to “requiring a 20% improvement in tender and swollen joint counts ● Added azathioprine and minocycline to prohibited medications list ● Allowed chloroquine to list of DMARDs ● Added absolute lymphocyte count to criteria for reduction and/or permanent discontinuation of study drug ● Revised definition of SAEs to include safety events of interest and their reporting requirements ● Other clarifications and administrative changes made. These changes to the protocol were made after the enrollment of 129 patients in RA25. Changes did not affect the overall outcome of the study.
    10 Jul 2014
    ● Revised discontinuation criteria for CPK and serum creatinine ● Revised increase and reduction in dose of study drug to allow patients to re-escalate back to 100 mg during the study ● Revised laboratory testing levels for CPK elevations and timeframe required for rechecks ● Updated background section to include final results from RA21 and RA22 studies ● Revised criteria to include additional instructions for discontinuing patients whose laboratory values met the Hematology Threshold Criteria ● Clarifications and other administrative changes made. These changes to the protocol were made after the enrollment of 611 patients in RA25. Changes did not affect the overall outcome of the study.
    24 Mar 2015
    ● Removed biomarker analysis and optional mRNA samples from study design ● Added additional discontinuation criteria to mandate that those patients who had not achieved low disease activity, experienced moderate or high disease activity for 2 consecutive visits after achieving low disease activity or remission, received a diagnosis of congenital short QT syndrome or experienced a QTc < 300 ms would be discontinued ● Added calculation of Clinical Disease Activity Index (CDAI) to arthritis assessments ● Clarifications and other administrative changes made. These changes to the protocol were made after the enrollment of 611 patients in RA25. Changes did not affect the overall outcome of the study.

    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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