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    Clinical Trial Results:
    A Multicentre, Double-blind, Randomized, Placebo Controlled, Parallel Group, Phase 3, Safety Extension Study to Evaluate the Safety and Tolerability of Tezepelumab in Adults and Adolescents with Severe Uncontrolled Asthma (DESTINATION)

    Summary
    EudraCT number
    		 2018-002501-53
    Trial protocol
    		 DE   FR   AT   PL  
    Global end of trial date
    30 Jun 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    25 May 2023
    First version publication date
    15 Dec 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    D5180C00018
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03706079
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    151 85, Södertälje, Sweden,
    Public contact
    Global Clinical Head, AstraZeneca AB, +1 302 885 1180, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Head, AstraZeneca AB, +1 302 885 1180, information.center@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
    09 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety and tolerability of Tezepelumab in severe asthma subjects
    Protection of trial subjects
    The protocol, protocol amendments, informed consent form (ICF), Investigator Brochure (IB), and other relevant documents (eg, advertisements) were submitted to an Institutional Review Board/Independent Ethics Committee (IRB/IEC) by the Investigator and reviewed and approved by the IRB/IEC before the study was initiated. The Investigator or his/her representative explained the nature of the study to the subject or his/her legally authorised representative and answered all questions regarding the study. Subjects were informed that their participation was voluntary. Subjects were required to sign a statement of informed consent that met the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study centre. The medical record must have included a statement that written informed consent was obtained before the subject was enrolled in the study and the date the written consent was obtained. The authorised person obtaining the informed consent must have also signed the ICF. Subjects must have been re-consented to the most current version of the ICF(s) during their participation in the study. A copy of the ICF(s) was provided to the subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jan 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 102
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Brazil: 93
    Country: Number of subjects enrolled
    Canada: 36
    Country: Number of subjects enrolled
    France: 41
    Country: Number of subjects enrolled
    Germany: 132
    Country: Number of subjects enrolled
    Israel: 47
    Country: Number of subjects enrolled
    Japan: 97
    Country: Number of subjects enrolled
    Korea, Republic of: 147
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Russian Federation: 51
    Country: Number of subjects enrolled
    Saudi Arabia: 7
    Country: Number of subjects enrolled
    South Africa: 109
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    United States: 203
    Country: Number of subjects enrolled
    Ukraine: 41
    Country: Number of subjects enrolled
    Viet Nam: 20
    Country: Number of subjects enrolled
    Turkey: 17
    Worldwide total number of subjects
    1209
    EEA total number of subjects
    211
    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)
    82
    Adults (18-64 years)
    927
    From 65 to 84 years
    200
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants who completed treatment and attended end of treatment visit in predecessor studies NAVIGATOR (NCT03347279) and SOURCE (NCT03406078) were eligible. In the predecessor studies, a total of 1059 and 150 subjects were randomised and dosed in the NAVIGATOR and SOURCE study respectively.

    Pre-assignment
    Screening details
    		 In this long-term extension study, 950 subjects were randomised and dosed with tezepelumab or placebo. The patients receiving tezepelumab in the predecessors continued to receive tezepelumab, while patients receiving placebo in the predecessors were re-randomized to either tezepelumab or placebo in the extension study

    Period 1
    Period 1 title
    Predecessor Study
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NAVIGATOR Rand Teze
    Arm description
    		 All subjects randomised to tezepelumab in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tezepelumab administered every 4 weeks subcutaneously
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    210 mg Q4W

    Arm title
    		 NAVIGATOR Rand Pbo
    Arm description
    		 All subjects randomised to placebo in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo administered every 4 weeks subcutaneously
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Q4W

    Arm title
    		 SOURCE Rand Teze
    Arm description
    		 All subjects randomised to tezepelumab in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tezepelumab administered every 4 weeks subcutaneously
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    210 mg Q4W

    Arm title
    		 SOURCE Rand Pbo
    Arm description
    		 All subjects randomised to placebo in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo administered every 4 weeks subcutaneously
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Q4W

    Number of subjects in period 1
    		NAVIGATOR Rand Teze NAVIGATOR Rand Pbo SOURCE Rand Teze SOURCE Rand Pbo
    Started
    528
    531
    74
    76
    Completed
    513
    509
    68
    73
    Not completed
    15
    22
    6
    3
         Adverse event, serious fatal
    -
    2
    1
    -
         Consent withdrawn by subject
    8
    15
    5
    2
         Did not complete safety follow-up visits
    2
    3
    -
    -
         Lost to follow-up
    5
    2
    -
    1
    Period 2
    Period 2 title
    Long Term Extension Study
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NAVIGATOR Rand Teze
    Arm description
    		 All subjects randomised to tezepelumab in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tezepelumab administered every 4 weeks subcutaneously
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    210 mg Q4W

    Arm title
    		 NAVIGATOR Rand Pbo
    Arm description
    		 All subjects randomised to placebo in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo administered every 4 weeks subcutaneously
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Q4W

    Arm title
    		 SOURCE Rand Teze
    Arm description
    		 All subjects randomised to tezepelumab in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tezepelumab administered every 4 weeks subcutaneously
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    210 mg Q4W

    Arm title
    		 SOURCE Rand Pbo
    Arm description
    		 All subjects randomised to placebo in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo administered every 4 weeks subcutaneously
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Q4W

    Number of subjects in period 2 [1]
    		NAVIGATOR Rand Teze NAVIGATOR Rand Pbo SOURCE Rand Teze SOURCE Rand Pbo
    Started
    415
    412
    60
    64
    Completed
    400
    398
    58
    59
    Not completed
    15
    14
    2
    5
         Adverse event, serious fatal
    8
    4
    1
    -
         Consent withdrawn by subject
    3
    6
    1
    3
         Did not complete safety follow-up visits
    1
    2
    -
    -
         Pregnancy
    1
    -
    -
    -
         Lost to follow-up
    2
    2
    -
    1
         Due to COVID-19 pandemic
    -
    -
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not everyone who completed predecessors was eligible or consented to participate in DESTINATION. However all patients randomized in the predecessor studies are included in the analysis.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NAVIGATOR Rand Teze
    Reporting group description
    		 All subjects randomised to tezepelumab in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.

    Reporting group title
    NAVIGATOR Rand Pbo
    Reporting group description
    		 All subjects randomised to placebo in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.

    Reporting group title
    SOURCE Rand Teze
    Reporting group description
    		 All subjects randomised to tezepelumab in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.

    Reporting group title
    SOURCE Rand Pbo
    Reporting group description
    		 All subjects randomised to placebo in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.

    Reporting group values
    		 NAVIGATOR Rand Teze NAVIGATOR Rand Pbo SOURCE Rand Teze SOURCE Rand Pbo Total
    Number of subjects
    		 528 531 74 76 1209
    Age Categorical
    Units: Participants
        <=18 years
    		 41 41 0 0 82
        Between 18 and 65 years
    		 391 416 58 62 927
        >=65 years
    		 96 74 16 14 200
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 49.9 ( 16.3 ) 49.0 ( 15.9 ) 53.5 ( 12.1 ) 53.4 ( 11.9 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 335 337 49 45 766
        Male
    		 193 194 25 31 443
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 83 81 10 14 188
        Not Hispanic or Latino
    		 445 450 64 62 1021
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 0 1
        Asian
    		 146 149 11 11 317
        Black of African American
    		 30 31 1 0 62
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 0 1
        Other
    		 19 23 0 1 43
        White
    		 332 327 62 64 785

    End points

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    End points reporting groups
    Reporting group title
    NAVIGATOR Rand Teze
    Reporting group description
    		 All subjects randomised to tezepelumab in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.

    Reporting group title
    NAVIGATOR Rand Pbo
    Reporting group description
    		 All subjects randomised to placebo in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.

    Reporting group title
    SOURCE Rand Teze
    Reporting group description
    		 All subjects randomised to tezepelumab in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.

    Reporting group title
    SOURCE Rand Pbo
    Reporting group description
    		 All subjects randomised to placebo in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.
    Reporting group title
    NAVIGATOR Rand Teze
    Reporting group description
    		 All subjects randomised to tezepelumab in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.

    Reporting group title
    NAVIGATOR Rand Pbo
    Reporting group description
    		 All subjects randomised to placebo in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.

    Reporting group title
    SOURCE Rand Teze
    Reporting group description
    		 All subjects randomised to tezepelumab in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.

    Reporting group title
    SOURCE Rand Pbo
    Reporting group description
    		 All subjects randomised to placebo in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.

    Primary: Exposure adjusted incidence rates of AEs/SAEs

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    End point title
    		 Exposure adjusted incidence rates of AEs/SAEs [1]
    End point description
    Includes adverse events with an onset date between the date of first dose of IP in the predecessor and minimum (date of last dose of IP + 33 days, date of death, date of study withdrawal, day prior to start of another biologic). The analysis is based on the Safety Analysis Set. Exposure adjusted rates are defined as number of subjects with AEs divided by total time at risk across all subjects, multiplied by 100
    End point type
    Primary
    End point timeframe
    Baseline (Week 0 in predecessor study) to Week 104. For subjects switching treatments from placebo in the predecessor to tezepelumab in DESTINATION, all data collected after first dose in the LTE part are excluded.
    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: Primary analysis was descriptive only, no hypothesis testing per the SAP
    End point values
    		 NAVIGATOR Rand Teze NAVIGATOR Rand Pbo SOURCE Rand Teze SOURCE Rand Pbo
    Number of subjects analysed
    528
    531
    74
    76
    Units: Incidence rate (per 100 years)
    number (not applicable)
        Total time at risk in years across all subjects
    917.0
    699.0
    129.4
    100.0
        Any AE incidence rate
    49.62
    62.66
    47.15
    69.97
        Any AE with outcome=death incidence rate
    0.76
    0.14
    1.55
    0.00
        Any SAE incidence rate
    7.85
    12.45
    13.14
    17.99
        AE leading to discontinuation of IP incidence rate
    1.64
    3.00
    1.55
    2.00
    No statistical analyses for this end point

    Secondary: Annualized asthma exacerbation rate (AAER)

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    End point title
    		 Annualized asthma exacerbation rate (AAER)
    End point description
    The annualized exacerbation rate is based on exacerbations reported by the investigator in the eCRF. The analysis is based on the primary population (Full Analysis Set)
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0 in predecessor study) to Week 104. For subjects switching treatments from placebo in the predecessor to tezepelumab in DESTINATION, all data collected after first dose in the LTE part are excluded.
    End point values
    		 NAVIGATOR Rand Teze NAVIGATOR Rand Pbo SOURCE Rand Teze SOURCE Rand Pbo
    Number of subjects analysed
    528
    531
    74
    76
    Units: events per year
        least squares mean (confidence interval 95%)
    0.82 (0.71 to 0.95)
    1.93 (1.70 to 2.20)
    1.07 (0.76 to 1.51)
    1.76 (1.27 to 2.45)
    Statistical analysis title
    		 Rand Teze vs Rand Pbo in NAVIGATOR patients
    Comparison groups
    NAVIGATOR Rand Pbo v NAVIGATOR Rand Teze
    Number of subjects included in analysis
    1059
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Rate Ratio
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 0.51
    Statistical analysis title
    		 Rand Teze vs Rand Pbo in SOURCE patients
    Comparison groups
    SOURCE Rand Teze v SOURCE Rand Pbo
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Rate Ratio
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.96

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Week 0 in predecessor study) to long-term extension completion (either weeks 104 or 116). Includes AEs with onset date between the date of first dose of IP and and the long-term extension completion or withdrawal date (on-study period)
    Adverse event reporting additional description
    For subjects switching treatments from placebo in the predecessor to tezepelumab in DESTINATION, all data collected after first dose in the LTE part are exluded. Note the primary objective in the End Points section presents on-treatment safety as opposed to on-study safety.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    SOURCE Rand Pbo
    Reporting group description
    		 All subjects randomised to placebo in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.

    Reporting group title
    NAVIGATOR Rand Teze
    Reporting group description
    		 All subjects randomised to tezepelumab in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.

    Reporting group title
    NAVIGATOR Rand Pbo
    Reporting group description
    		 All subjects randomised to placebo in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION.

    Reporting group title
    SOURCE Rand Teze
    Reporting group description
    		 All subjects randomised to tezepelumab in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study.

    Serious adverse events
    		 SOURCE Rand Pbo NAVIGATOR Rand Teze NAVIGATOR Rand Pbo SOURCE Rand Teze
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 76 (25.00%)
    82 / 528 (15.53%)
    94 / 531 (17.70%)
    18 / 74 (24.32%)
         number of deaths (all causes)
    0
    8
    5
    2
         number of deaths resulting from adverse events
    0
    8
    5
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    2 / 531 (0.38%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Colon adenoma
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Colorectal cancer
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Endometrial cancer
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    1 / 74 (1.35%)
         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
    Neurilemmoma benign
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 528 (0.38%)
    0 / 531 (0.00%)
    0 / 74 (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
    Prostate cancer
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Uterine leiomyoma
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    1 / 74 (1.35%)
         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 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Prostatic adenoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Thymoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    0 / 74 (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
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Thrombosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Haematoma
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Cyanosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 528 (0.38%)
    0 / 531 (0.00%)
    0 / 74 (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
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Death
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    3 / 531 (0.56%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Drug hypersensitivity
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Ovarian cyst
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Uterine prolapse
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    8 / 76 (10.53%)
    16 / 528 (3.03%)
    43 / 531 (8.10%)
    5 / 74 (6.76%)
         occurrences causally related to treatment / all
    0 / 12
    2 / 20
    0 / 91
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    0 / 74 (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
    Haemothorax
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Epistaxis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Nasal polyps
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eosinophilic pneumonia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Disruptive mood dysregulation disorder
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Hip fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Incisional hernia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    1 / 74 (1.35%)
         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
    Lower limb fracture
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Ligament rupture
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 528 (0.57%)
    0 / 531 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Periprocedural myocardial infarction
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Radius fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Skin laceration
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Spinal compression fracture
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    0 / 74 (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
    Road traffic accident
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Ulna fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Tendon rupture
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Congenital, familial and genetic disorders
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    1 / 74 (1.35%)
         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
    Prinzmetal angina
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    1 / 74 (1.35%)
         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
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Acute myocardial infarction
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 528 (0.38%)
    0 / 531 (0.00%)
    0 / 74 (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
    Atrial flutter
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Cardiac arrest
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    1 / 74 (1.35%)
         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
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    1 / 74 (1.35%)
         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 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 528 (0.38%)
    0 / 531 (0.00%)
    0 / 74 (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
    Coronary artery disease
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 528 (0.38%)
    0 / 531 (0.00%)
    0 / 74 (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
    Coronary artery occlusion
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Aortic valve stenosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Palpitations
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Cubital tunnel syndrome
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Headache
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Migraine
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Idiopathic generalised epilepsy
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Myelopathy
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Seizure
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Blood and lymphatic system disorders
    Immune thrombocytopenia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    2 / 531 (0.38%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Anal fistula
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Inguinal hernia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    2 / 531 (0.38%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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 ischaemic
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Large intestine polyp
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Obstruction gastric
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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 / 76 (0.00%)
    1 / 528 (0.19%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Rectal haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    1 / 76 (1.32%)
    1 / 528 (0.19%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Oesophageal achalasia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    0 / 74 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 528 (0.38%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Rash
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    1 / 531 (0.19%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerulonephritis membranous
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Nephrolithiasis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    1 / 74 (1.35%)
         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
    Ureterolithiasis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Hyperparathyroidism primary
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Musculoskeletal and connective tissue disorders
    Amyotrophy
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    0 / 74 (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
    Arthralgia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    1 / 74 (1.35%)
         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
    Bone cyst
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Arthritis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    0 / 74 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Muscle necrosis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    0 / 74 (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
    Myositis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Osteoarthritis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Spondylolisthesis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Breast abscess
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Cellulitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    2 / 531 (0.38%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    2 / 531 (0.38%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 528 (0.38%)
    1 / 531 (0.19%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Herpes zoster oticus
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Influenza
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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 discitis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    1 / 74 (1.35%)
         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
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    2 / 531 (0.38%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Lung abscess
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Periorbital cellulitis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Pneumonia bacterial
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 528 (0.57%)
    2 / 531 (0.38%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 528 (0.19%)
    1 / 531 (0.19%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Pneumonia viral
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Septic shock
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 528 (0.38%)
    1 / 531 (0.19%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    COVID-19
         subjects affected / exposed
    1 / 76 (1.32%)
    3 / 528 (0.57%)
    2 / 531 (0.38%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 528 (0.57%)
    2 / 531 (0.38%)
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 528 (0.00%)
    0 / 531 (0.00%)
    0 / 74 (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
    Meningitis bacterial
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Atypical pneumonia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Pneumonia aspiration
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Sepsis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 528 (0.19%)
    0 / 531 (0.00%)
    0 / 74 (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
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    1 / 74 (1.35%)
         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
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 528 (0.00%)
    1 / 531 (0.19%)
    0 / 74 (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
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 SOURCE Rand Pbo NAVIGATOR Rand Teze NAVIGATOR Rand Pbo SOURCE Rand Teze
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 76 (73.68%)
    369 / 528 (69.89%)
    376 / 531 (70.81%)
    51 / 74 (68.92%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 76 (1.32%)
    14 / 528 (2.65%)
    9 / 531 (1.69%)
    3 / 74 (4.05%)
         occurrences all number
    1
    20
    10
    4
    Fall
         subjects affected / exposed
    4 / 76 (5.26%)
    9 / 528 (1.70%)
    12 / 531 (2.26%)
    3 / 74 (4.05%)
         occurrences all number
    4
    9
    12
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 76 (9.21%)
    30 / 528 (5.68%)
    26 / 531 (4.90%)
    5 / 74 (6.76%)
         occurrences all number
    7
    39
    40
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 76 (13.16%)
    58 / 528 (10.98%)
    54 / 531 (10.17%)
    9 / 74 (12.16%)
         occurrences all number
    12
    157
    101
    16
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    6 / 76 (7.89%)
    26 / 528 (4.92%)
    25 / 531 (4.71%)
    0 / 74 (0.00%)
         occurrences all number
    6
    28
    29
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 76 (3.95%)
    7 / 528 (1.33%)
    2 / 531 (0.38%)
    2 / 74 (2.70%)
         occurrences all number
    3
    8
    3
    2
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 76 (2.63%)
    9 / 528 (1.70%)
    8 / 531 (1.51%)
    3 / 74 (4.05%)
         occurrences all number
    3
    9
    9
    3
    Nausea
         subjects affected / exposed
    1 / 76 (1.32%)
    16 / 528 (3.03%)
    9 / 531 (1.69%)
    1 / 74 (1.35%)
         occurrences all number
    1
    19
    10
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    9 / 76 (11.84%)
    14 / 528 (2.65%)
    25 / 531 (4.71%)
    6 / 74 (8.11%)
         occurrences all number
    16
    17
    27
    7
    Nasal polyps
         subjects affected / exposed
    5 / 76 (6.58%)
    0 / 528 (0.00%)
    4 / 531 (0.75%)
    1 / 74 (1.35%)
         occurrences all number
    7
    0
    6
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 76 (0.00%)
    30 / 528 (5.68%)
    22 / 531 (4.14%)
    0 / 74 (0.00%)
         occurrences all number
    0
    39
    31
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 76 (0.00%)
    4 / 528 (0.76%)
    9 / 531 (1.69%)
    3 / 74 (4.05%)
         occurrences all number
    0
    4
    12
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 76 (3.95%)
    27 / 528 (5.11%)
    21 / 531 (3.95%)
    2 / 74 (2.70%)
         occurrences all number
    4
    46
    23
    2
    Back pain
         subjects affected / exposed
    2 / 76 (2.63%)
    36 / 528 (6.82%)
    25 / 531 (4.71%)
    3 / 74 (4.05%)
         occurrences all number
    2
    49
    30
    4
    Myalgia
         subjects affected / exposed
    1 / 76 (1.32%)
    12 / 528 (2.27%)
    11 / 531 (2.07%)
    5 / 74 (6.76%)
         occurrences all number
    2
    15
    13
    7
    Pain in extremity
         subjects affected / exposed
    0 / 76 (0.00%)
    18 / 528 (3.41%)
    11 / 531 (2.07%)
    2 / 74 (2.70%)
         occurrences all number
    0
    21
    12
    2
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 76 (0.00%)
    16 / 528 (3.03%)
    16 / 531 (3.01%)
    0 / 74 (0.00%)
         occurrences all number
    0
    23
    26
    0
    Bronchitis
         subjects affected / exposed
    3 / 76 (3.95%)
    29 / 528 (5.49%)
    39 / 531 (7.34%)
    9 / 74 (12.16%)
         occurrences all number
    3
    44
    51
    10
    Chronic sinusitis
         subjects affected / exposed
    4 / 76 (5.26%)
    9 / 528 (1.70%)
    6 / 531 (1.13%)
    3 / 74 (4.05%)
         occurrences all number
    4
    13
    8
    4
    Bronchitis bacterial
         subjects affected / exposed
    7 / 76 (9.21%)
    30 / 528 (5.68%)
    19 / 531 (3.58%)
    8 / 74 (10.81%)
         occurrences all number
    10
    34
    24
    20
    Gastroenteritis
         subjects affected / exposed
    1 / 76 (1.32%)
    25 / 528 (4.73%)
    16 / 531 (3.01%)
    2 / 74 (2.70%)
         occurrences all number
    1
    26
    17
    2
    Pharyngitis
         subjects affected / exposed
    2 / 76 (2.63%)
    26 / 528 (4.92%)
    23 / 531 (4.33%)
    0 / 74 (0.00%)
         occurrences all number
    2
    35
    28
    0
    Oral candidiasis
         subjects affected / exposed
    6 / 76 (7.89%)
    12 / 528 (2.27%)
    15 / 531 (2.82%)
    5 / 74 (6.76%)
         occurrences all number
    11
    16
    17
    6
    Nasopharyngitis
         subjects affected / exposed
    22 / 76 (28.95%)
    130 / 528 (24.62%)
    124 / 531 (23.35%)
    18 / 74 (24.32%)
         occurrences all number
    38
    220
    222
    27
    Rhinitis
         subjects affected / exposed
    2 / 76 (2.63%)
    18 / 528 (3.41%)
    21 / 531 (3.95%)
    4 / 74 (5.41%)
         occurrences all number
    2
    24
    42
    4
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 76 (11.84%)
    72 / 528 (13.64%)
    91 / 531 (17.14%)
    12 / 74 (16.22%)
         occurrences all number
    9
    131
    151
    13
    Sinusitis bacterial
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 528 (0.38%)
    1 / 531 (0.19%)
    5 / 74 (6.76%)
         occurrences all number
    1
    2
    1
    5
    Sinusitis
         subjects affected / exposed
    5 / 76 (6.58%)
    30 / 528 (5.68%)
    43 / 531 (8.10%)
    2 / 74 (2.70%)
         occurrences all number
    6
    34
    64
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 76 (1.32%)
    29 / 528 (5.49%)
    29 / 531 (5.46%)
    1 / 74 (1.35%)
         occurrences all number
    2
    50
    33
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 76 (3.95%)
    24 / 528 (4.55%)
    17 / 531 (3.20%)
    2 / 74 (2.70%)
         occurrences all number
    3
    31
    23
    5
    COVID-19
         subjects affected / exposed
    1 / 76 (1.32%)
    7 / 528 (1.33%)
    8 / 531 (1.51%)
    5 / 74 (6.76%)
         occurrences all number
    1
    8
    8
    5
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    1 / 76 (1.32%)
    8 / 528 (1.52%)
    2 / 531 (0.38%)
    3 / 74 (4.05%)
         occurrences all number
    1
    10
    6
    3
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 76 (2.63%)
    16 / 528 (3.03%)
    8 / 531 (1.51%)
    1 / 74 (1.35%)
         occurrences all number
    2
    16
    9
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 May 2019
    Amended Inclusion/ exclusion criteria, clarification on dose preparation/administration, updated randomization and blinding procedures. Additional ‘vaping products’ added as restricted during the study. Asthma Control Questionnaire removed from visit 2 onwards, in degrees Celsius removed as units of body temperature, updated paternal exposure.
    10 Jan 2020
    CSP Version 3.0 was submitted to the FDA but was not implemented due to the identification of aspects needing to be corrected/clarified. The CSP Version 3.0 was not submitted to any other regulatory authorities and/or IRB/IEC. After further update and revision, the CSP changes were fully implemented as CSP Version 4.0. Study phrase ‘the extension study’ replaced with ‘Long Term Extension Study’ or ‘LTE’ throughout the protocol. Schedule of activities, table 1 updated with additional assessments and footnotes. Primary and exploratory objectives updated. Dupilumab added as approved medication for severe asthma with an eosinophilic phenotype. Updated inclusion/exclusion criteria for subjects. Procedures for discontinuation of study treatment updated. Added the maximum amount of blood collected from subjects that are a part of extended follow-up. Updated statistical, safety and other analyses.
    06 Mar 2020
    Addition of multiple assessments to correct omission in previous CSP amendment. Addition of ‘weight’ assessment, ’12-lead ECG’ assessment and ‘urine pregnancy test, dipstick’. Removal of ‘serum pregnancy test’ assessment. Revised maximum amount of blood collected from subjects a part of extended follow-up.
    02 Jun 2020
    Informed consent names changed from ‘Addendum to Informed Consent’ to ‘Addendum for Extended Follow-up to Informed Consent’ throughout the protocol for consistency. Added appendix H to describe in more detail the changes made during the COVID-19 pandemic. Inclusion criteria updated, prohibited medications section updated, clarification on restrictions throughout the course of the study for alcohol, tobacco and other. Added reference to Appendix H for guidance on safety assessments during the COVID-19 pandemic. General instructions added to follow the local regulations/guidance during the COVID-19 pandemic. Revised text in Asthma Control Questionnaire and St George’s Respiratory Questionnaire.
    12 Apr 2021
    Assessment blood RNA transcript profiling, transcriptomics added to further clarify the biomarkers collected during the study. Independent adjudication committee updated to clarify that ER visit, urgent care visit and hospitalization visits will be assessed by independent adjudication committee until completion of follow-up or extended follow-up. Clarification on concomitant therapy and biologics introduction following week 116 provided. Added guidance for COVID-19 vaccination in the study. Revised wording to clarify PK sample analysis process in 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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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