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    Clinical Trial Results:
    An Open Label, Multicenter Extension Study to Evaluate the Safety of R935788 in Patients with Rheumatoid Arthritis Who Have Completed the Treatment Phase of a Rigel-Sponsored R935788 Study

    Summary
    EudraCT number
    2008-000744-13
    Trial protocol
    DE   BE   FR   IT   BG  
    Global end of trial date
    21 Aug 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Feb 2017
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C-935788-012
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00805467
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca Pharmaceuticals
    Sponsor organisation address
    Alderley Park, Macclesfield, United Kingdom,
    Public contact
    Neil Mackillop, AstraZeneca, information.center@astrazeneca.com
    Scientific contact
    Neil Mackillop, AstraZeneca, neil.mackillop@astrazeneca.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
    11 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Aug 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Aug 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to investigate the long-term safety of fostamatinib in patients with RA who completed the treatment phase of Study C-788-006X, C-788-010, or C-788-011.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practices (GCPs) and applicable laws and regulations. Patients provided their written consent to participate in the study after having been informed about the nature and purpose of the study, participation/termination conditions, and risks and benefits of treatment prior to admission to this study. The study was approved by an Independent Ethics Committee/Institutional Review Board (IEC/IRB) before the start of the study.
    Background therapy
    Patients may receive stable doses of methotrexate (with folic or folinic acid), azathioprine (not in combination with methotrexate), leflunomide (not in combination with methotrexate), sulfasalazine, chloroquine, hydroxychloroquine, gold, NSAIDs (including COX2 inhibitors), minocycline, or doxycycline.
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Aug 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Scientific research
    Long term follow-up duration
    6 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Colombia: 146
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Mexico: 127
    Country: Number of subjects enrolled
    Peru: 7
    Country: Number of subjects enrolled
    Poland: 61
    Country: Number of subjects enrolled
    Romania: 20
    Country: Number of subjects enrolled
    United States: 226
    Worldwide total number of subjects
    624
    EEA total number of subjects
    118
    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)
    513
    From 65 to 84 years
    110
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 624 patients were enrolled: 1, 59, 183 & 381 were allocated to the 50mg twice daily (bid), 100 mg once daily (qd), 150 mg qd and 100 mg bid groups, respectively. As this was a long-term extension study no specific end date was given. Patients who were ongoing when the study was terminated are shown as completers.

    Pre-assignment
    Screening details
    Treatments were assigned according to those given in the qualifying studies. All patients received investigational product.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This an open label extension study, but patients will remain blinded to their treatment assignment from the previous feeder study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fostamatinib 50 mg bid
    Arm description
    Oral treatment
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50mg twice daily

    Arm title
    Fostamatinib 100 mg qd
    Arm description
    Oral treatment
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg once daily

    Arm title
    Fostamatinib 150 mg qd
    Arm description
    Oral treatment
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150mg once daily

    Arm title
    Fostamatinib 100 mg bid
    Arm description
    Oral treatment
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg twice daily

    Number of subjects in period 1
    Fostamatinib 50 mg bid Fostamatinib 100 mg qd Fostamatinib 150 mg qd Fostamatinib 100 mg bid
    Started
    1
    59
    183
    381
    Completed
    1
    25
    80
    144
    Not completed
    0
    34
    103
    237
         Protocol deviation
    -
    3
    -
    5
         Physician decision
    -
    1
    2
    6
         Lack of efficacy
    -
    8
    13
    86
         Not reported
    -
    -
    3
    7
         Adverse event, serious fatal
    -
    2
    7
    5
         Adverse event, non-fatal
    -
    13
    26
    57
         Consent withdrawn by subject
    -
    6
    45
    50
         Lost to follow-up
    -
    1
    7
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fostamatinib 50 mg bid
    Reporting group description
    Oral treatment

    Reporting group title
    Fostamatinib 100 mg qd
    Reporting group description
    Oral treatment

    Reporting group title
    Fostamatinib 150 mg qd
    Reporting group description
    Oral treatment

    Reporting group title
    Fostamatinib 100 mg bid
    Reporting group description
    Oral treatment

    Reporting group values
    Fostamatinib 50 mg bid Fostamatinib 100 mg qd Fostamatinib 150 mg qd Fostamatinib 100 mg bid Total
    Number of subjects
    1 59 183 381 624
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    0 52 151 310 513
        From 65-84 years
    1 7 32 70 110
        85 years and over
    0 0 0 1 1
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    70 ± 0 51.4 ± 11.15 51.7 ± 13.32 53.8 ± 12.36 -
    Gender, Male/Female
    Units: Participants
        Female
    1 53 157 324 535
        Male
    0 6 26 57 89
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    0 18 88 184 290
        Black
    1 1 6 14 22
        Hispanic
    0 40 88 179 307
        Asian
    0 0 0 2 2
        Other
    0 0 1 2 3

    End points

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    End points reporting groups
    Reporting group title
    Fostamatinib 50 mg bid
    Reporting group description
    Oral treatment

    Reporting group title
    Fostamatinib 100 mg qd
    Reporting group description
    Oral treatment

    Reporting group title
    Fostamatinib 150 mg qd
    Reporting group description
    Oral treatment

    Reporting group title
    Fostamatinib 100 mg bid
    Reporting group description
    Oral treatment

    Primary: Percentage of patients who had at least 1 treatment emergent adverse event in any category

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    End point title
    Percentage of patients who had at least 1 treatment emergent adverse event in any category [1]
    End point description
    AE = adverse event, bid = twice daily, IP = investigational product, qd = once daily, SAE = serious adverse event
    End point type
    Primary
    End point timeframe
    Entry in extension to end of study, up to a maximum of 5 years. (Variable by subject - median duration of 3 years)
    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: Data not avaliable as it is observational study.
    End point values
    Fostamatinib 50 mg bid Fostamatinib 100 mg qd Fostamatinib 150 mg qd Fostamatinib 100 mg bid
    Number of subjects analysed
    1
    59
    183
    381
    Units: % of patients
    number (not applicable)
        Any AE
    100
    91.5
    90.7
    88.7
        Any fatal AE
    0
    1.7
    3.8
    1.6
        Any SAE (including fatal AEs)
    100
    3.4
    18.6
    20.2
        Any AE leading to termination of study therapy
    0
    22
    16.4
    15.2
    No statistical analyses for this end point

    Secondary: DAS28-CRP score

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    End point title
    DAS28-CRP score
    End point description
    The Disease Activity Score 28 using C-Reactive Protein (DAS28-CRP) is a measure of disease activity in rheumatoid arthritis (RA) and assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). These measures are then fed into a complex mathematical formula to produce the overall DAS on a scale from 1 to 10, where scores greater than 5.1 are considered to indicate active disease, scores less than 3.2 are considered to indicate with well controlled disease, and scores less than 2.6 are considered to indicate remission. bid = twice daily, CRP = C-reactive protein, DAS28 = Disease Activity Score based on a 28 joint count, n/a = not applicable, qd = once daily
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    Fostamatinib 50 mg bid Fostamatinib 100 mg qd Fostamatinib 150 mg qd Fostamatinib 100 mg bid
    Number of subjects analysed
    1 [2]
    55
    181
    374
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline (n=1, 55, 181, 374)
    5.27 ± 0
    5.34 ± 1.123
    5.31 ± 1.162
    5.36 ± 1.259
        Quarter 4 (n=1, 41, 136, 254)
    2 ± 0
    3.57 ± 1.408
    3.46 ± 1.282
    3.44 ± 1.453
        Quarter 8 (n=1, 33, 114, 201)
    2.92 ± 0
    3.43 ± 1.412
    3.25 ± 1.29
    3.35 ± 1.484
        Quarter 12 (n=1, 30, 94, 174)
    2.31 ± 0
    3.36 ± 1.376
    3.07 ± 1.055
    3.27 ± 1.373
    Notes
    [2] - Standard deviation not applicable for a single patient. 0 entered.
    No statistical analyses for this end point

    Secondary: HAQ-DI score

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    End point title
    HAQ-DI score
    End point description
    Health Assessment Questionnaire - Disability Index, a measure of physical function. The HAQ-DI score is calculated by summing the category scores from 8 sub-categories (ie, scores for patient ability in dressing and grooming, rising, eating, walking, hygeine, reach, grip and common daily activities) and dividing by the number of categories completed. The HAQ-DI score takes values between 0 and 3, with a higher score indicating greater disability. A HAQ-DI response is a reduction from baseline in HAQ-DI greater than or equal to the minimally important difference (0.22). BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once a day.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    Fostamatinib 50 mg bid Fostamatinib 100 mg qd Fostamatinib 150 mg qd Fostamatinib 100 mg bid
    Number of subjects analysed
    1 [3]
    56
    181
    376
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Baseline (n=1, 56, 181, 376)
    1.25 ± 0
    1.5 ± 0.735
    1.46 ± 0.707
    1.46 ± 0.715
        Quarter 4 (n=1, 41, 138, 254)
    0.57 ± 0
    1 ± 0.677
    1.07 ± 0.726
    0.99 ± 0.722
        Quarter 8 (n=1, 33, 107, 201)
    0.43 ± 0
    1 ± 0.657
    1.02 ± 0.72
    0.95 ± 0.703
        Quarter 12 (n=1, 30, 94, 176)
    0.38 ± 0
    1.01 ± 0.651
    0.98 ± 0.718
    0.96 ± 0.687
    Notes
    [3] - Standard deviation not applicable for a single patient. 0 entered.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    As this was an ongoing long term extension study the timeframe for adverse reporting is from the start of the study (August 2008) until study termination (August 2013).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    100 MG QD
    Reporting group description
    Fostamatinib 100mg once daily

    Reporting group title
    100 MG BID
    Reporting group description
    Fostamatinib 100mg twice daily

    Reporting group title
    50 MG BID
    Reporting group description
    Fostamatinib 50mg twice daily

    Reporting group title
    150 MG QD
    Reporting group description
    Fostamatinib 150mg once daily

    Serious adverse events
    100 MG QD 100 MG BID 50 MG BID 150 MG QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 59 (3.39%)
    77 / 381 (20.21%)
    1 / 1 (100.00%)
    34 / 183 (18.58%)
         number of deaths (all causes)
    1
    6
    0
    7
         number of deaths resulting from adverse events
    0
    1
    0
    3
    Vascular disorders
    AORTIC ANEURYSM
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ARTERIOSCLEROSIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    IMPLANTABLE DEFIBRILLATOR INSERTION
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HIP ARTHROPLASTY
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    KNEE ARTHROPLASTY
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ANAL CANCER
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRAIN NEOPLASM MALIGNANT
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    BASOSQUAMOUS CARCINOMA OF SKIN
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CERVIX CARCINOMA
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLON CANCER STAGE IV
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIFFUSE LARGE B-CELL LYMPHOMA
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LARGE INTESTINE CARCINOMA
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUNG SQUAMOUS CELL CARCINOMA STAGE UNSPECIFIED
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PARATHYROID TUMOUR BENIGN
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THYROID CANCER
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTERINE LEIOMYOMA
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    ABORTION SPONTANEOUS INCOMPLETE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABORTION SPONTANEOUS
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEVICE DISLOCATION
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUDDEN DEATH
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    OVARIAN CYST
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENDOMETRIAL HYPERTROPHY
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POSTMENOPAUSAL HAEMORRHAGE
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VAGINAL PROLAPSE
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    DISLOCATION OF VERTEBRA
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MUSCLE RUPTURE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    JOINT DISLOCATION
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PUBIS FRACTURE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ARTERIOSPASM CORONARY
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIOPULMONARY FAILURE
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTRACARDIAC THROMBUS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR DYSFUNCTION
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    ASTHMA
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    1 / 1 (100.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUNG INFILTRATION
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY FIBROSIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THROMBOTIC THROMBOCYTOPENIC PURPURA
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Nervous system disorders
    ACUTE POLYNEUROPATHY
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    ISCHAEMIC STROKE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUMBAR RADICULOPATHY
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RADICULOPATHY
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PRESYNCOPE
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    PANOPHTHALMITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 59 (0.00%)
    3 / 381 (0.79%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLONIC POLYP
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLITIS MICROSCOPIC
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIVERTICULUM
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FAECALOMA
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRIC PERFORATION
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HIATUS HERNIA
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL PERFORATION
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS HAEMORRHAGIC
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RECTAL PROLAPSE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UMBILICAL HERNIA
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    1 / 1 (100.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    RENAL FAILURE ACUTE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATIC CIRRHOSIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATIC STEATOSIS
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    CERVICAL SPINAL STENOSIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUMBAR SPINAL STENOSIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOSITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPINAL OSTEOARTHRITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    GOITRE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    0 / 59 (0.00%)
    3 / 381 (0.79%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ABSCESS SOFT TISSUE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BURSITIS INFECTIVE
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    4 / 381 (1.05%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS HEPATITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS INFECTION
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSENTERY
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EPIGLOTTITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ERYTHEMA MIGRANS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ESCHERICHIA SEPSIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GIARDIASIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTED BITES
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOBAR PNEUMONIA
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENINGITIS BACTERIAL
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NECROTISING FASCIITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA STAPHYLOCOCCAL
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 59 (0.00%)
    6 / 381 (1.57%)
    0 / 1 (0.00%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 7
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    1 / 1 (100.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SINUSITIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VARICELLA
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION STAPHYLOCOCCAL
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    100 MG QD 100 MG BID 50 MG BID 150 MG QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 59 (83.05%)
    306 / 381 (80.31%)
    1 / 1 (100.00%)
    141 / 183 (77.05%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    10 / 59 (16.95%)
    62 / 381 (16.27%)
    0 / 1 (0.00%)
    26 / 183 (14.21%)
         occurrences all number
    13
    82
    0
    31
    General disorders and administration site conditions
    OEDEMA PERIPHERAL
         subjects affected / exposed
    3 / 59 (5.08%)
    24 / 381 (6.30%)
    0 / 1 (0.00%)
    7 / 183 (3.83%)
         occurrences all number
    3
    34
    0
    8
    CHEST PAIN
         subjects affected / exposed
    3 / 59 (5.08%)
    6 / 381 (1.57%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences all number
    3
    6
    0
    0
    Investigations
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 59 (0.00%)
    6 / 381 (1.57%)
    1 / 1 (100.00%)
    2 / 183 (1.09%)
         occurrences all number
    0
    10
    1
    5
    BLOOD PRESSURE INCREASED
         subjects affected / exposed
    1 / 59 (1.69%)
    27 / 381 (7.09%)
    0 / 1 (0.00%)
    11 / 183 (6.01%)
         occurrences all number
    1
    35
    0
    11
    TRANSAMINASES INCREASED
         subjects affected / exposed
    7 / 59 (11.86%)
    35 / 381 (9.19%)
    0 / 1 (0.00%)
    15 / 183 (8.20%)
         occurrences all number
    8
    45
    0
    16
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 59 (1.69%)
    24 / 381 (6.30%)
    0 / 1 (0.00%)
    13 / 183 (7.10%)
         occurrences all number
    1
    28
    0
    17
    NEUTROPENIA
         subjects affected / exposed
    5 / 59 (8.47%)
    30 / 381 (7.87%)
    0 / 1 (0.00%)
    10 / 183 (5.46%)
         occurrences all number
    5
    34
    0
    13
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    2 / 59 (3.39%)
    15 / 381 (3.94%)
    1 / 1 (100.00%)
    8 / 183 (4.37%)
         occurrences all number
    2
    18
    1
    9
    ASTHMA
         subjects affected / exposed
    0 / 59 (0.00%)
    4 / 381 (1.05%)
    1 / 1 (100.00%)
    1 / 183 (0.55%)
         occurrences all number
    0
    6
    1
    1
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    4 / 59 (6.78%)
    33 / 381 (8.66%)
    0 / 1 (0.00%)
    23 / 183 (12.57%)
         occurrences all number
    7
    49
    0
    35
    Eye disorders
    CONJUNCTIVITIS
         subjects affected / exposed
    3 / 59 (5.08%)
    11 / 381 (2.89%)
    0 / 1 (0.00%)
    5 / 183 (2.73%)
         occurrences all number
    3
    11
    0
    5
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    3 / 59 (5.08%)
    10 / 381 (2.62%)
    0 / 1 (0.00%)
    3 / 183 (1.64%)
         occurrences all number
    3
    10
    0
    4
    DIARRHOEA
         subjects affected / exposed
    20 / 59 (33.90%)
    96 / 381 (25.20%)
    0 / 1 (0.00%)
    60 / 183 (32.79%)
         occurrences all number
    36
    151
    0
    93
    GASTRITIS
         subjects affected / exposed
    5 / 59 (8.47%)
    14 / 381 (3.67%)
    0 / 1 (0.00%)
    8 / 183 (4.37%)
         occurrences all number
    5
    15
    0
    8
    DYSPEPSIA
         subjects affected / exposed
    3 / 59 (5.08%)
    8 / 381 (2.10%)
    1 / 1 (100.00%)
    3 / 183 (1.64%)
         occurrences all number
    4
    8
    1
    4
    NAUSEA
         subjects affected / exposed
    3 / 59 (5.08%)
    27 / 381 (7.09%)
    0 / 1 (0.00%)
    11 / 183 (6.01%)
         occurrences all number
    4
    31
    0
    12
    VOMITING
         subjects affected / exposed
    5 / 59 (8.47%)
    23 / 381 (6.04%)
    0 / 1 (0.00%)
    10 / 183 (5.46%)
         occurrences all number
    9
    27
    0
    11
    HAEMORRHOIDS
         subjects affected / exposed
    4 / 59 (6.78%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 183 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Renal and urinary disorders
    HYPERTONIC BLADDER
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 381 (0.52%)
    1 / 1 (100.00%)
    0 / 183 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Skin and subcutaneous tissue disorders
    SKIN LESION
         subjects affected / exposed
    3 / 59 (5.08%)
    4 / 381 (1.05%)
    0 / 1 (0.00%)
    2 / 183 (1.09%)
         occurrences all number
    3
    4
    0
    2
    RASH
         subjects affected / exposed
    3 / 59 (5.08%)
    9 / 381 (2.36%)
    0 / 1 (0.00%)
    8 / 183 (4.37%)
         occurrences all number
    3
    10
    0
    9
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    1 / 59 (1.69%)
    17 / 381 (4.46%)
    0 / 1 (0.00%)
    10 / 183 (5.46%)
         occurrences all number
    2
    25
    0
    16
    BACK PAIN
         subjects affected / exposed
    3 / 59 (5.08%)
    30 / 381 (7.87%)
    0 / 1 (0.00%)
    9 / 183 (4.92%)
         occurrences all number
    3
    35
    0
    11
    BURSITIS
         subjects affected / exposed
    4 / 59 (6.78%)
    16 / 381 (4.20%)
    0 / 1 (0.00%)
    5 / 183 (2.73%)
         occurrences all number
    5
    20
    0
    5
    OSTEOARTHRITIS
         subjects affected / exposed
    3 / 59 (5.08%)
    10 / 381 (2.62%)
    0 / 1 (0.00%)
    2 / 183 (1.09%)
         occurrences all number
    3
    10
    0
    2
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    3 / 59 (5.08%)
    38 / 381 (9.97%)
    0 / 1 (0.00%)
    10 / 183 (5.46%)
         occurrences all number
    6
    69
    0
    16
    TENDONITIS
         subjects affected / exposed
    4 / 59 (6.78%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    2 / 183 (1.09%)
         occurrences all number
    4
    3
    0
    2
    Metabolism and nutrition disorders
    HYPERLIPIDAEMIA
         subjects affected / exposed
    3 / 59 (5.08%)
    3 / 381 (0.79%)
    0 / 1 (0.00%)
    1 / 183 (0.55%)
         occurrences all number
    3
    3
    0
    1
    HYPOKALAEMIA
         subjects affected / exposed
    3 / 59 (5.08%)
    9 / 381 (2.36%)
    0 / 1 (0.00%)
    2 / 183 (1.09%)
         occurrences all number
    3
    16
    0
    2
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    3 / 59 (5.08%)
    26 / 381 (6.82%)
    0 / 1 (0.00%)
    14 / 183 (7.65%)
         occurrences all number
    4
    38
    0
    20
    NASOPHARYNGITIS
         subjects affected / exposed
    3 / 59 (5.08%)
    27 / 381 (7.09%)
    0 / 1 (0.00%)
    10 / 183 (5.46%)
         occurrences all number
    3
    31
    0
    12
    PHARYNGITIS
         subjects affected / exposed
    5 / 59 (8.47%)
    16 / 381 (4.20%)
    0 / 1 (0.00%)
    5 / 183 (2.73%)
         occurrences all number
    6
    19
    0
    6
    INFLUENZA
         subjects affected / exposed
    8 / 59 (13.56%)
    36 / 381 (9.45%)
    0 / 1 (0.00%)
    18 / 183 (9.84%)
         occurrences all number
    15
    54
    0
    20
    SINUSITIS
         subjects affected / exposed
    3 / 59 (5.08%)
    26 / 381 (6.82%)
    0 / 1 (0.00%)
    4 / 183 (2.19%)
         occurrences all number
    3
    37
    0
    4
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    7 / 59 (11.86%)
    51 / 381 (13.39%)
    1 / 1 (100.00%)
    20 / 183 (10.93%)
         occurrences all number
    8
    76
    1
    29
    URINARY TRACT INFECTION
         subjects affected / exposed
    12 / 59 (20.34%)
    72 / 381 (18.90%)
    0 / 1 (0.00%)
    28 / 183 (15.30%)
         occurrences all number
    32
    125
    0
    45

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Nov 2008
    The addition of an independent data monitoring committee. Additional vital signs data collection.
    18 Apr 2011
    Removed restrictions on male contraception and sperm donation. Described ongoing cardiovascular event adjudication. Updated treatment period to allow investigator to reduce visit frequency to once every 3 months for patients stable on treatment.

    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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